Pain relief in children: pharmacokinetic extrapolation supported by real-world evidence

Pain relief in children: pharmacokinetic extrapolation supported by real-world evidence | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pain relief in children: pharmacokinetic extrapolation supported by real-world evidence John Chi Keung Lai, Stefanie Rasche, Nicola Fish, Kerstin Wagner, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3835340/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Relieving pain quickly in children suffering from childhood aches and pains is high priority for parents and caregivers. However, conducting controlled pain relief studies in children to investigate the time it takes for the onset of pain relief presents ethical and reproducibility considerations. The aim of this work was to research the ability of paracetamol pain relievers to quickly (in under 30 minutes) relieve pain in pediatric populations. Methods Onset of pain relief in children aged 6 years and above was determined using a pharmacokinetic/pharmacodynamic model to extrapolate data from adults who were treated with paracetamol in clinical studies. Perception of pain relief in 2- to 5-year-old children was collected via questionnaire from caregivers who had administered paracetamol to their child for pain. Results Pharmacokinetic/pharmacodynamic modeling generated with data from paracetamol adult pain relief studies and pharmacokinetic studies of paracetamol fast dissolving tablet and suspension demonstrated that the onset of pain relief would be reached within 30 minutes in children 6 years and above. In the 2- to 5-year-old group, 89% of parents and caregivers perceived their child felt relief from pain in less than 30 minutes after being administered paracetamol pain reliever. Conclusions Paracetamol-containing pain reliever in tablet and suspension formulations provide relief from pain in less than 30 minutes in the pediatric population. Biological sciences/Biological techniques Health sciences/Biomarkers/Predictive markers Health sciences/Health care/Paediatrics Pain pediatric population paracetamol real world evidence pharmacokinetics Figures Figure 1 Figure 2 Figure 3 Background Pain, such as headache, toothache, earache, teething pain, sore throat, pain from colds and influenza, as well as general aches and pains are common in infants and children [ ]. This vulnerable population relies on caregivers to recognize their pain and determine the appropriate course of action to alleviate it. For situations that warrant the use of an over the counter (OTC) pain reliever, delivering fast pain relief to children in pain is of highest priority for caregivers. Several randomized controlled trials (RCTs) demonstrate the onset of pain relief from paracetamol in under 30 minutes in adults [ , , , ]. However, investigating speed of pain relief in pediatric populations in RCTs presents ethical considerations of exposing children to unnecessary pain [ ]. Furthermore, there are challenges in objectively determining pain intensity in small children who cannot express themselves in a manner that is reproducible for investigators, creating the potential for variability in clinical interventions. Other methods are needed to increase our understanding of pain relief in children. In the work presented here, we use two methods to investigate the speed of pain relief onset from paracetamol (acetaminophen) products in children. The first method was to use data from onset of pain relief and pharmacokinetic (PK) studies in adults to predict the onset of pain relief in children. A panel from a U.S. Food and Drug Administration workshop agreed that there is ample basis to justify extrapolation of efficacy of paracetamol from an adult to a pediatric population [ , , ]. In addition, there is a precedence of conducting adult-to-pediatric data extrapolations as a surrogate to RCTs of pain in children [ , ]. The second method was using Real World Evidence (RWE) to assess the speed of pain relief perception reported by caregivers of children aged 2 to 5 years old. RWE, as discussed by the consumer healthcare Proprietary Association of Great Britain (PAGB) [ ], has been used, for example, to show improvements in infants with colic and diaper rash [ , ]. A consortium of companies that manufacture OTC medicines posit that RWE can help healthcare professionals and regulatory bodies make decisions about the use of nonprescription medicines and can fill in gaps that have not been addressed in RCTs [ ]. The aim of this work was to research the ability of paracetamol pain relievers to quickly (defined as in under 30 minutes) relieve pain in pediatric populations. Methods Pharmacokinetic (PK) data from healthy adults was used to research the speed of pain relief from a paracetamol suspension (Calpol® Six Plus Suspension) and a fast-dissolving tablet (Calpol® Fastmelt Tablet), designed for use for children aged 6 and above [ , ]. A correlation between plasma concentration of paracetamol and the perception of pain relief was previously established using a pharmacokinetic/pharmacodynamic (PK/PD) model based on PK data from different paracetamol tablet formulations (Tylenol Extra Strength Caplet and others) [ ]. Pharmacodynamics is a branch of medical science that shows how the biological processes respond to the drug in the body. Pharmacokinetics provide inferences on how a drug is absorbed, distributed, metabolized and excreted in the body over time. The PK/PD model linked concentrations of paracetamol over time to the onset of confirmed perceptible pain relief (CPPR) and concluded that an earlier onset of CPPR was correlated to a faster rate of paracetamol absorption. Furthermore, the model showed that the expected time to CPPR for Tylenol Extra Strength Caplets was less than 30 minutes, confirming observations from clinical trials. In the current research, the PK profiles of the paracetamol products in adult populations were used to predict the PK profiles in children 6 years and above, adjusting for body weight and dosing regimen differences [ ]. The resulting PK profiles in children were then applied to the PK/PD model to determine the onset of pain relief. PK/PD modeling for the 2- to 5-year-old age group was not attempted due to the lack of supporting pharmacokinetic and clinical data for infant suspension formulations. See Fig. 1 for a graphic representation of the data extrapolation and model steps. To explore the timing for pain relief in children under age 6, we conducted a noninterventional, retrospective study to collect RWE from primary caregivers on their perception of time to pain relief in their child after administering paracetamol (Calpol® Infant Suspension, 120mg per 5mL) at home in response to the child’s pain in children aged 2 to 5 years old. The noninterventional study, conducted in the UK between November 19, 2021, and January 7, 2022, included 513 primary caregivers with children aged 2 to 5 years old. They were required to have purchased a paracetamol suspension (Calpol® Infant Suspension) on their own and administered it to their child for pain relief as directed on the product label within one month of participating in the study. Children were required to be healthy except for mild to moderate pain for which they were treated, with no fever, or underlying chronic health conditions. No treatment with other medications at the same time was permitted. All methods in both the previously conducted adult PK trial and the non-interventional RWE study were carried out in accordance with relevant guidelines and regulations. The adult PK trial was approved by Hopital Ambroise Pare Ethics Committee. The RWE study was approved by Reading Independent Ethics Committee. All participants in the adult PK trial and all legal guardians in the RWE study provided informed consent to participate. Of the adult participants, 91% were female. Most (58%) were aged 30–39, followed by 18-29-year-olds (26%). Ages of the children at the time of the study were: 2 years old (28%); 3 years old (17%); 4 years old (32%); and 5 years old (23%). Participants answered questions such as what condition they treated the child for, the time of day or night the child needed pain relief and the time it took for the caregiver to perceive the onset of pain relief in the child. Results Figure 2 shows the predicted PK profiles of the pediatric paracetamol suspension (Calpol® Six Plus Suspension) in the pediatric 6- to 12-year-old group. Figure 3 shows the predicted PK profiles of a pediatric paracetamol tablet (Calpol® Six Plus Fastmelt Tablet) in the pediatric 6- to 18-year-old group. In both products, the time to maximum plasma concentration (Tmax) of paracetamol was faster than that seen with Tylenol® Extra Strength Caplets. Since the PK/PD model established with Tylenol Extra Strength Caplets and two faster release tablets containing paracetamol demonstrated that Tmax of paracetamol was correlated with the onset of pain relief perception, both the pediatric paracetamol suspension and the pediatric paracetamol tablets for children aged 6 and older are expected to provide perceptible pain relief in less than 30 minutes, since both products have a shorter Tmax than Tylenol Extra Strength Caplets and Tylenol® Extra Strength Caplets have been observed in clinical studies to produce perceptible pain relief within 30 minutes. RWE collected in the noninterventional retrospective study showed that: 89% of caregivers reported that they perceived relief of pain in their child within 30 minutes of administration of the pediatric paracetamol suspension. The top pain conditions being treated were sore throat (32%), headache (30%), other aches and pains (27%) and earache (26%). Evening was the time of day when most people administered the medicine (42%), followed by morning (22%) and afternoon (21%), then during the night (15%) Safety There were no adverse events or product quality complaints reported by the caregivers in the noninterventional study in which we collected RWE. Since the PK/PD modeling used existing data, adverse events were not a factor. Discussion When a child is experiencing fever or pain from common childhood ailments, fast relief is a high priority for their caregiver. Previous research has shown that paracetamol can start to reduce fever in children in as little as 15 minutes [ ]. Relief of pain has been more difficult to measure in children and was the focus of this research. There is precedence of conducting adult-to-pediatric data extrapolation and modelling as a surrogate for pain clinical trials in children to seek approval for use of drug products in a pediatric population [7, 8, 9]. In addition, there is growing interest and acceptance in using real world evidence to show efficacy, especially in young populations that would present challenges in clinical trials [12, 13, 14]. There are, however, some limitations in these approaches. For example, the extrapolation of the data is predicated on certain assumptions of comparability between adults and children. Extrapolation to infant population often results in uncertainties since the drug metabolism pathway is not fully developed. This limitation does not apply to paracetamol since its metabolic pathways are matured by the first year of age [ ]. In the collection of RWE, the reporting of the onset of pain relief in children aged 2 through 5 is subjective based on the recollection of their caregivers. This potential recall bias was mitigated by limiting the time period for recalling their experience to four weeks, which is a realistic and acceptable time period. The potential to misclassify participation in the study was minimized by careful definition of pain types and therefore ruling out of children with conditions that would be difficult for caregivers, all of whom were laypersons, to clearly identify. Other measures such as validity checks were taken to ensure a robust study. Despite the potential for limitations from the extrapolation and RWE methods, clinical studies on pain relief in children are not a viable option. Based on RWE collected from caregivers responsible for pain relief in the children under their care, as well as the extrapolated data of time to pain relief after taking paracetamol, it can be concluded that pediatric paracetamol pain relievers relieve pain in children in less than 30 minutes. This was demonstrated in a population of children from 2 to 5 years old with a paracetamol infant suspension (Calpol® Infant Suspension, 120mg per 5mL) and extrapolated in children aged 6 to 12 years for a pediatric paracetamol suspension (Calpol® Six Plus Suspension, 250 mg per 5 mL) and children aged 6 to 18 years for a pediatric paracetamol tablet (Calpol® Six Plus Fastmelt Tablets, 250mg per tablet). Conclusions In this work, formulations of infant and pediatric paracetamol (Calpol®) demonstrated the ability to begin to reduce the pain associated with common childhood ailments in 30 minutes or less. Real World Evidence supports this conclusion in 2- to 5-year-old children who used the infant paracetamol suspension. PK extrapolation supports the same conclusion in children aged 6 and older who used paracetamol formulations (tablets and suspension) intended for pediatric use. Relieving pain as quickly as possible in children is a high priority for caregivers and healthcare professionals who treat pediatric populations. The various paracetamol formulations in this research have been shown to reduce pain in less than 30 minutes. This result can help caregivers of this vulnerable population to select the right OTC pain reliever. Abbreviations CPPR Confirmed perceptible pain relief OTC Over the counter PAGB Proprietary Association of Great Britain PD Pharmacodynamic PK Pharmacokinetic RCT Randomized controlled trial RWE Real World Evidence Tmax Time to maximum plasma concentration UK United Kingdom U.S. United States Declarations Consent for publication – not applicable Availability of data and materials - The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests - The authors are either employees or were paid for their services by the funding company, however, there are no competing interests related to this paper and its publication. Funding - This work was funded in full by Johnson & Johnson Consumer Inc. Authors’ contributions – JCKL analyzed and interpreted the PK/PD data for the extrapolation of adult data to pediatric use. SR, NF and JB oversaw and interpreted the data from the RWE questionnaire. KW and CS provided oversight of the research and background for the research program. All authors contributed to the writing of the manuscript and the analysis of results. All authors read and approved the final manuscript. Acknowledgements - Medical writing support for the preparation of this manuscript was provided by Carol Feinberg of Carol Feinberg Consulting LLC and was funded by Johnson & Johnson Consumer Inc. The authors would like to acknowledge Andrew Myers MD for critically reviewing the manuscript and providing guidance during the study. References Pain in children: Management. International Assoc for the Study of Pain 2019. https://www.iasp-pain.org/resources/fact-sheets/pain-in-children-management/ Yue Y, Collaku A, Brown J, Buchanan WL, Reed K, Cooper SA, Otto J. Efficacy and Speed of Onset of Pain Relief of Fast-Dissolving Paracetamol on Postsurgical Dental Pain: Two Randomized, Single-Dose, Double-Blind, Placebo-Controlled Clinical Studies. Clin Ther. 2013 Sep;35(9):1306-20. Yue Y et al. Two Randomized, Double-Blind, Placebo-Controlled Efficacy Studies Assessing the Efficacy and Speed of Onset of Pain Relief of Panadol Advance® In Post-Surgical Dental Pain. F19 Perioperative Pain – Other| Volume 13, Issue 4, Supplement, S85, April 01, 2012. Olson NZ, Otero AM, Marrero I, Tirado S, Cooper S, Doyle G, Jayawardena S, Sunshine A. Onset of Analgesia for Liquigel Ibuprofen 400 Mg, Acetaminophen 1000 Mg, Ketoprofen 25 Mg, And Placebo in The Treatment of Postoperative Dental Pain. J Clin Pharmacol. 2001 Nov;41(11):1238-47. Eyers S, Fingleton J, Perrin K, Beasley R. Proposed MHRA changes to UK children’s paracetamol dosing recommendations: modelling study. J R Soc Med. 2012;105(6):263–269. Bellieni CV, Johnston C. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. First published: 20 September 2015. https://doi.org/10.1111/apa.13210 Berde CB, Walco GA, Krane EJ, et al. Pediatric Analgesic Clinical Trial Designs, Measures and Extrapolation: Report of An FDA Scientific Workshop. Pediatrics. 2012; 129:354–364. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011 Nov;128(5):1242-9. Hertz S. Analgesic Development for Pediatric Patients. https://www.fda.gov/media/96805/download. Accessed 1 July 2021. Center for Drug Evaluation and Research Application Number: 022450orig1s000. Clinical Pharmacology and Biopharmaceutics Review(S) for Solution for Acetaminophen IV Injection. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022450Orig1s000ClinPharmR.pdf. Office of Clinical Pharmacology Review for NDA 022450 – Acetaminophen IV Injection. https://www.fda.gov/media/103521/download. Guidance: Real-World Evidence in the self-care environment: Definitions, applications, and practical guidance Issued: July 2021. Goldman M, Beaumont T. A real world evaluation of a treatment for infant colic based on the experience and perceptions of 4004 parents. British Journal of Nursing 2017, Vol 26. No 5 (Suppl 1). Goldman M, Lodhi I. A real-world evidence study evaluating a treatment for nappy rash. British Journal of Nursing, 2016, Vol 25, No 8. Csoke E, Landes S, Francis M., et al. How can real-world evidence aid decision making during the life cycle of nonprescription medicines? Clin Transl Sci. 2022;15:43–54. Bioavailability Study Report: A Comparison of the Bioavailability of Calpol Suspension Forte with that of Calpol Paediatric Suspension in Healthy Volunteers. 1980. Company Document Bioavailability Study Report No. 95 AP 325: Bioequivalence Study of a New Paracetamol Formulation Called Flashtab. 1995. Company Document. Lindauer A, Gisleskog PO, Gelotte C, Cheruvu N and Zimmerma B. Modeling and Simulation of Time to Pain Relief of a Fast-Absorbing Acetaminophen Formulation. Abstract for American Conference on Pharmacometrics 2017. Mahmood I. Dosing in Children: A Critical Review of the Pharmacokinetic Allometric Scaling and Modelling Approaches in Paediatric Drug Development and Clinical Settings. Clin Pharmacokinet (2014) 53:327–346. Johnson & Johnson LTD. Fast on Fever; Claim Substantiation for Calpol Infant and Calpol Six Plus Suspensions. October 2012. Available upon request. Lu H, Rosenbaum S. Developmental Pharmacokinetics in Pediatric Populations. J Pediatr Pharmacol Ther. 2014 Oct-Dec; 19(4): 262–276. Additional Declarations Competing interest reported. The authors are either employees or were paid for their services by the funding company, however, there are no competing interests related to this paper and its publication. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3835340","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":268881694,"identity":"c406c132-0e8e-43b1-835b-9bc94dad2810","order_by":0,"name":"John Chi Keung 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18:44:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68729,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of PK profiles of paracetamol suspension (Calpol® Six Plus) in adult and pediatric age groups vs. paracetamol caplets (Tylenol® Extra Strength)\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3835340/v1/841715f13b53264921c11938.jpg"},{"id":50228217,"identity":"8d72a21c-4347-485d-a9a1-0255926cb187","added_by":"auto","created_at":"2024-01-26 18:44:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":101027,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of PK profiles of paracetamol tablets (Calpol® Six Plus Fastmelts) in adult and pediatric age groups vs. paracetamol caplets (Tylenol® Extra Strength)\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3835340/v1/9a7a467fb9f03c8b331bc3d4.jpg"},{"id":60978384,"identity":"7b815562-5f54-47dc-b16b-ebdc088a6997","added_by":"auto","created_at":"2024-07-24 08:40:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":485156,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3835340/v1/280e357a-4239-4105-9789-9700cd798a9d.pdf"}],"financialInterests":"Competing interest reported. The authors are either employees or were paid for their services by the funding company, however, there are no competing interests related to this paper and its publication.","formattedTitle":"Pain relief in children: pharmacokinetic extrapolation supported by real-world evidence","fulltext":[{"header":"Background","content":"\u003cp\u003ePain, such as headache, toothache, earache, teething pain, sore throat, pain from colds and influenza, as well as general aches and pains are common in infants and children [\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e\u003c/a\u003e]. This vulnerable population relies on caregivers to recognize their pain and determine the appropriate course of action to alleviate it. For situations that warrant the use of an over the counter (OTC) pain reliever, delivering fast pain relief to children in pain is of highest priority for caregivers.\u003c/p\u003e \u003cp\u003eSeveral randomized controlled trials (RCTs) demonstrate the onset of pain relief from paracetamol in under 30 minutes in adults [\u003ca class=\"FNLink\" href=\"#Fn2\" id=\"#FNLinkFn2\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn3\" id=\"#FNLinkFn3\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn4\" id=\"#FNLinkFn4\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn5\" id=\"#FNLinkFn5\"\u003e\u003c/a\u003e]. However, investigating speed of pain relief in pediatric populations in RCTs presents ethical considerations of exposing children to unnecessary pain [\u003ca class=\"FNLink\" href=\"#Fn6\" id=\"#FNLinkFn6\"\u003e\u003c/a\u003e]. Furthermore, there are challenges in objectively determining pain intensity in small children who cannot express themselves in a manner that is reproducible for investigators, creating the potential for variability in clinical interventions. Other methods are needed to increase our understanding of pain relief in children. In the work presented here, we use two methods to investigate the speed of pain relief onset from paracetamol (acetaminophen) products in children.\u003c/p\u003e \u003cp\u003eThe first method was to use data from onset of pain relief and pharmacokinetic (PK) studies in adults to predict the onset of pain relief in children. A panel from a U.S. Food and Drug Administration workshop agreed that there is ample basis to justify extrapolation of efficacy of paracetamol from an adult to a pediatric population [\u003ca class=\"FNLink\" href=\"#Fn7\" id=\"#FNLinkFn7\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn8\" id=\"#FNLinkFn8\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn9\" id=\"#FNLinkFn9\"\u003e\u003c/a\u003e]. In addition, there is a precedence of conducting adult-to-pediatric data extrapolations as a surrogate to RCTs of pain in children [\u003ca class=\"FNLink\" href=\"#Fn10\" id=\"#FNLinkFn10\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn11\" id=\"#FNLinkFn11\"\u003e\u003c/a\u003e].\u003c/p\u003e \u003cp\u003eThe second method was using Real World Evidence (RWE) to assess the speed of pain relief perception reported by caregivers of children aged 2 to 5 years old. RWE, as discussed by the consumer healthcare Proprietary Association of Great Britain (PAGB) [\u003ca class=\"FNLink\" href=\"#Fn12\" id=\"#FNLinkFn12\"\u003e\u003c/a\u003e], has been used, for example, to show improvements in infants with colic and diaper rash [\u003ca class=\"FNLink\" href=\"#Fn13\" id=\"#FNLinkFn13\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn14\" id=\"#FNLinkFn14\"\u003e\u003c/a\u003e]. A consortium of companies that manufacture OTC medicines posit that RWE can help healthcare professionals and regulatory bodies make decisions about the use of nonprescription medicines and can fill in gaps that have not been addressed in RCTs [\u003ca class=\"FNLink\" href=\"#Fn15\" id=\"#FNLinkFn15\"\u003e\u003c/a\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this work was to research the ability of paracetamol pain relievers to quickly (defined as in under 30 minutes) relieve pain in pediatric populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePharmacokinetic (PK) data from healthy adults was used to research the speed of pain relief from a paracetamol suspension (Calpol\u0026reg; Six Plus Suspension) and a fast-dissolving tablet (Calpol\u0026reg; Fastmelt Tablet), designed for use for children aged 6 and above [\u003ca class=\"FNLink\" href=\"#Fn16\" id=\"#FNLinkFn16\"\u003e\u003c/a\u003e, \u003ca class=\"FNLink\" href=\"#Fn17\" id=\"#FNLinkFn17\"\u003e\u003c/a\u003e].\u003c/p\u003e \u003cp\u003eA correlation between plasma concentration of paracetamol and the perception of pain relief was previously established using a pharmacokinetic/pharmacodynamic (PK/PD) model based on PK data from different paracetamol tablet formulations (Tylenol Extra Strength Caplet and others) [\u003ca class=\"FNLink\" href=\"#Fn18\" id=\"#FNLinkFn18\"\u003e\u003c/a\u003e]. Pharmacodynamics is a branch of medical science that shows how the biological processes respond to the drug in the body. Pharmacokinetics provide inferences on how a drug is absorbed, distributed, metabolized and excreted in the body over time. The PK/PD model linked concentrations of paracetamol over time to the onset of confirmed perceptible pain relief (CPPR) and concluded that an earlier onset of CPPR was correlated to a faster rate of paracetamol absorption. Furthermore, the model showed that the expected time to CPPR for Tylenol Extra Strength Caplets was less than 30 minutes, confirming observations from clinical trials.\u003c/p\u003e \u003cp\u003eIn the current research, the PK profiles of the paracetamol products in adult populations were used to predict the PK profiles in children 6 years and above, adjusting for body weight and dosing regimen differences [\u003ca class=\"FNLink\" href=\"#Fn19\" id=\"#FNLinkFn19\"\u003e\u003c/a\u003e]. The resulting PK profiles in children were then applied to the PK/PD model to determine the onset of pain relief. PK/PD modeling for the 2- to 5-year-old age group was not attempted due to the lack of supporting pharmacokinetic and clinical data for infant suspension formulations. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for a graphic representation of the data extrapolation and model steps.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo explore the timing for pain relief in children under age 6, we conducted a noninterventional, retrospective study to collect RWE from primary caregivers on their perception of time to pain relief in their child after administering paracetamol (Calpol\u0026reg; Infant Suspension, 120mg per 5mL) at home in response to the child\u0026rsquo;s pain in children aged 2 to 5 years old.\u003c/p\u003e \u003cp\u003eThe noninterventional study, conducted in the UK between November 19, 2021, and January 7, 2022, included 513 primary caregivers with children aged 2 to 5 years old. They were required to have purchased a paracetamol suspension (Calpol\u0026reg; Infant Suspension) on their own and administered it to their child for pain relief as directed on the product label within one month of participating in the study. Children were required to be healthy except for mild to moderate pain for which they were treated, with no fever, or underlying chronic health conditions. No treatment with other medications at the same time was permitted.\u003c/p\u003e \u003cp\u003e All methods in both the previously conducted adult PK trial and the non-interventional RWE study were carried out in accordance with relevant guidelines and regulations. The adult PK trial was approved by Hopital Ambroise Pare Ethics Committee. The RWE study was approved by Reading Independent Ethics Committee. All participants in the adult PK trial and all legal guardians in the RWE study provided informed consent to participate.\u003c/p\u003e \u003cp\u003eOf the adult participants, 91% were female. Most (58%) were aged 30\u0026ndash;39, followed by 18-29-year-olds (26%). Ages of the children at the time of the study were: 2 years old (28%); 3 years old (17%); 4 years old (32%); and 5 years old (23%).\u003c/p\u003e \u003cp\u003eParticipants answered questions such as what condition they treated the child for, the time of day or night the child needed pain relief and the time it took for the caregiver to perceive the onset of pain relief in the child.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the predicted PK profiles of the pediatric paracetamol suspension (Calpol\u0026reg; Six Plus Suspension) in the pediatric 6- to 12-year-old group. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the predicted PK profiles of a pediatric paracetamol tablet (Calpol\u0026reg; Six Plus Fastmelt Tablet) in the pediatric 6- to 18-year-old group. In both products, the time to maximum plasma concentration (Tmax) of paracetamol was faster than that seen with Tylenol\u0026reg; Extra Strength Caplets. Since the PK/PD model established with Tylenol Extra Strength Caplets and two faster release tablets containing paracetamol demonstrated that Tmax of paracetamol was correlated with the onset of pain relief perception, both the pediatric paracetamol suspension and the pediatric paracetamol tablets for children aged 6 and older are expected to provide perceptible pain relief in less than 30 minutes, since both products have a shorter Tmax than Tylenol Extra Strength Caplets and Tylenol\u0026reg; Extra Strength Caplets have been observed in clinical studies to produce perceptible pain relief within 30 minutes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRWE collected in the noninterventional retrospective study showed that:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e89% of caregivers reported that they perceived relief of pain in their child within 30 minutes of administration of the pediatric paracetamol suspension.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe top pain conditions being treated were sore throat (32%), headache (30%), other aches and pains (27%) and earache (26%).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEvening was the time of day when most people administered the medicine (42%), followed by morning (22%) and afternoon (21%), then during the night (15%)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eThere were no adverse events or product quality complaints reported by the caregivers in the noninterventional study in which we collected RWE. Since the PK/PD modeling used existing data, adverse events were not a factor.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhen a child is experiencing fever or pain from common childhood ailments, fast relief is a high priority for their caregiver. Previous research has shown that paracetamol can start to reduce fever in children in as little as 15 minutes [\u003ca class=\"FNLink\" href=\"#Fn20\" id=\"#FNLinkFn20\"\u003e\u003c/a\u003e]. Relief of pain has been more difficult to measure in children and was the focus of this research.\u003c/p\u003e \u003cp\u003eThere is precedence of conducting adult-to-pediatric data extrapolation and modelling as a surrogate for pain clinical trials in children to seek approval for use of drug products in a pediatric population [7, 8, 9]. In addition, there is growing interest and acceptance in using real world evidence to show efficacy, especially in young populations that would present challenges in clinical trials [12, 13, 14].\u003c/p\u003e \u003cp\u003eThere are, however, some limitations in these approaches. For example, the extrapolation of the data is predicated on certain assumptions of comparability between adults and children. Extrapolation to infant population often results in uncertainties since the drug metabolism pathway is not fully developed. This limitation does not apply to paracetamol since its metabolic pathways are matured by the first year of age [\u003ca class=\"FNLink\" href=\"#Fn21\" id=\"#FNLinkFn21\"\u003e\u003c/a\u003e].\u003c/p\u003e \u003cp\u003eIn the collection of RWE, the reporting of the onset of pain relief in children aged 2 through 5 is subjective based on the recollection of their caregivers. This potential recall bias was mitigated by limiting the time period for recalling their experience to four weeks, which is a realistic and acceptable time period. The potential to misclassify participation in the study was minimized by careful definition of pain types and therefore ruling out of children with conditions that would be difficult for caregivers, all of whom were laypersons, to clearly identify. Other measures such as validity checks were taken to ensure a robust study.\u003c/p\u003e \u003cp\u003eDespite the potential for limitations from the extrapolation and RWE methods, clinical studies on pain relief in children are not a viable option. Based on RWE collected from caregivers responsible for pain relief in the children under their care, as well as the extrapolated data of time to pain relief after taking paracetamol, it can be concluded that pediatric paracetamol pain relievers relieve pain in children in less than 30 minutes. This was demonstrated in a population of children from 2 to 5 years old with a paracetamol infant suspension (Calpol\u0026reg; Infant Suspension, 120mg per 5mL) and extrapolated in children aged 6 to 12 years for a pediatric paracetamol suspension (Calpol\u0026reg; Six Plus Suspension, 250 mg per 5 mL) and children aged 6 to 18 years for a pediatric paracetamol tablet (Calpol\u0026reg; Six Plus Fastmelt Tablets, 250mg per tablet).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this work, formulations of infant and pediatric paracetamol (Calpol\u0026reg;) demonstrated the ability to begin to reduce the pain associated with common childhood ailments in 30 minutes or less. Real World Evidence supports this conclusion in 2- to 5-year-old children who used the infant paracetamol suspension. PK extrapolation supports the same conclusion in children aged 6 and older who used paracetamol formulations (tablets and suspension) intended for pediatric use.\u003c/p\u003e \u003cp\u003eRelieving pain as quickly as possible in children is a high priority for caregivers and healthcare professionals who treat pediatric populations. The various paracetamol formulations in this research have been shown to reduce pain in less than 30 minutes. This result can help caregivers of this vulnerable population to select the right OTC pain reliever.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCPPR \u0026nbsp; \u0026nbsp;\u0026nbsp;Confirmed perceptible pain relief\u003c/p\u003e\n\u003cp\u003eOTC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Over the counter\u003c/p\u003e\n\u003cp\u003ePAGB \u0026nbsp; \u0026nbsp;Proprietary Association of Great Britain\u003c/p\u003e\n\u003cp\u003ePD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pharmacodynamic\u003c/p\u003e\n\u003cp\u003ePK \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pharmacokinetic\u003c/p\u003e\n\u003cp\u003eRCT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Randomized controlled trial\u003c/p\u003e\n\u003cp\u003eRWE\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Real World Evidence\u003c/p\u003e\n\u003cp\u003eTmax\u0026nbsp; \u0026nbsp;\u0026nbsp;Time to maximum plasma concentration\u003c/p\u003e\n\u003cp\u003eUK\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;United Kingdom\u003c/p\u003e\n\u003cp\u003eU.S. \u0026nbsp; \u0026nbsp; \u0026nbsp; United States\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u0026ndash; not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e- The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e- The authors are either employees or were paid for their services by the funding company, however, there are no competing interests related to this paper and its publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding -\u0026nbsp;\u003c/strong\u003eThis work was funded in full by Johnson \u0026amp; Johnson Consumer Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u0026ndash; JCKL analyzed and interpreted the PK/PD data for the extrapolation of adult data to pediatric use. SR, NF and JB oversaw and interpreted the data from the RWE questionnaire. KW and CS provided oversight of the research and background for the research program. All authors contributed to the writing of the manuscript and the analysis of results. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e- Medical writing support for the preparation of this manuscript was provided by Carol Feinberg of Carol Feinberg Consulting LLC and was funded by Johnson \u0026amp; Johnson Consumer Inc. The authors would like to acknowledge Andrew Myers MD for critically reviewing the manuscript and providing guidance during the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePain in children: Management. International Assoc for the Study of Pain 2019. https://www.iasp-pain.org/resources/fact-sheets/pain-in-children-management/\u003c/li\u003e\n\u003cli\u003eYue Y, Collaku A, Brown J, Buchanan WL, Reed K, Cooper SA, Otto J. Efficacy and Speed of Onset of Pain Relief of Fast-Dissolving Paracetamol on Postsurgical Dental Pain: Two Randomized, Single-Dose, Double-Blind, Placebo-Controlled Clinical Studies. Clin Ther. 2013 Sep;35(9):1306-20. \u003c/li\u003e\n\u003cli\u003eYue Y et al. Two Randomized, Double-Blind, Placebo-Controlled Efficacy Studies Assessing the Efficacy and Speed of Onset of Pain Relief of Panadol Advance\u0026reg; In Post-Surgical Dental Pain. F19 Perioperative Pain \u0026ndash; Other| Volume 13, Issue 4, Supplement, S85, April 01, 2012. \u003c/li\u003e\n\u003cli\u003eOlson NZ, Otero AM, Marrero I, Tirado S, Cooper S, Doyle G, Jayawardena S, Sunshine A. Onset of Analgesia for Liquigel Ibuprofen 400 Mg, Acetaminophen 1000 Mg, Ketoprofen 25 Mg, And Placebo in The Treatment of Postoperative Dental Pain. J Clin Pharmacol. 2001 Nov;41(11):1238-47.\u003c/li\u003e\n\u003cli\u003eEyers S, Fingleton J, Perrin K, Beasley R. Proposed MHRA changes to UK children\u0026rsquo;s paracetamol dosing recommendations: modelling study. \u003cem\u003eJ R Soc Med. \u003c/em\u003e2012;105(6):263\u0026ndash;269. \u003c/li\u003e\n\u003cli\u003eBellieni CV, Johnston C. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. First published: 20 September 2015. https://doi.org/10.1111/apa.13210\u003c/li\u003e\n\u003cli\u003eBerde CB, Walco GA, Krane EJ, et al. Pediatric Analgesic Clinical Trial Designs, Measures and Extrapolation: Report of An FDA Scientific Workshop. Pediatrics. 2012; 129:354\u0026ndash;364.\u003c/li\u003e\n\u003cli\u003eDunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011 Nov;128(5):1242-9.\u003c/li\u003e\n\u003cli\u003eHertz S. Analgesic Development for Pediatric Patients. https://www.fda.gov/media/96805/download. Accessed 1 July 2021.\u003c/li\u003e\n\u003cli\u003eCenter for Drug Evaluation and Research Application Number: 022450orig1s000. Clinical Pharmacology and Biopharmaceutics Review(S) for Solution for Acetaminophen IV Injection. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022450Orig1s000ClinPharmR.pdf.\u003c/li\u003e\n\u003cli\u003eOffice of Clinical Pharmacology Review for NDA 022450 \u0026ndash; Acetaminophen IV Injection. https://www.fda.gov/media/103521/download.\u003c/li\u003e\n\u003cli\u003eGuidance: Real-World Evidence in the self-care environment: Definitions, applications, and practical guidance Issued: July 2021.\u003c/li\u003e\n\u003cli\u003eGoldman M, Beaumont T. A real world evaluation of a treatment for infant colic based on the experience and perceptions of 4004 parents. British Journal of Nursing 2017, Vol 26. No 5 (Suppl 1).\u003c/li\u003e\n\u003cli\u003eGoldman M, Lodhi I. A real-world evidence study evaluating a treatment for nappy rash. British Journal of Nursing, 2016, Vol 25, No 8.\u003c/li\u003e\n\u003cli\u003eCsoke E, Landes S, Francis M., et al. How can real-world evidence aid decision making during the life cycle of nonprescription medicines? Clin Transl Sci. 2022;15:43\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eBioavailability Study Report: A Comparison of the Bioavailability of Calpol Suspension Forte with that of Calpol Paediatric Suspension in Healthy Volunteers. 1980. Company Document\u003c/li\u003e\n\u003cli\u003eBioavailability Study Report No. 95 AP 325: Bioequivalence Study of a New Paracetamol Formulation Called Flashtab. 1995. Company Document.\u003c/li\u003e\n\u003cli\u003eLindauer A, Gisleskog PO, Gelotte C, Cheruvu N and Zimmerma B. Modeling and Simulation of Time to Pain Relief of a Fast-Absorbing Acetaminophen Formulation. Abstract for American Conference on Pharmacometrics 2017.\u003c/li\u003e\n\u003cli\u003eMahmood I. Dosing in Children: A Critical Review of the Pharmacokinetic Allometric Scaling and Modelling Approaches in Paediatric Drug Development and Clinical Settings. Clin Pharmacokinet (2014) 53:327\u0026ndash;346. \u003c/li\u003e\n\u003cli\u003eJohnson \u0026amp; Johnson LTD. Fast on Fever; Claim Substantiation for Calpol Infant and Calpol Six Plus Suspensions. October 2012. Available upon request. \u003c/li\u003e\n\u003cli\u003eLu H, Rosenbaum S. Developmental Pharmacokinetics in Pediatric Populations. J Pediatr Pharmacol Ther. 2014 Oct-Dec; 19(4): 262\u0026ndash;276.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pain, pediatric population, paracetamol, real world evidence, pharmacokinetics","lastPublishedDoi":"10.21203/rs.3.rs-3835340/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3835340/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRelieving pain quickly in children suffering from childhood aches and pains is high priority for parents and caregivers. However, conducting controlled pain relief studies in children to investigate the time it takes for the onset of pain relief presents ethical and reproducibility considerations. The aim of this work was to research the ability of paracetamol pain relievers to quickly (in under 30 minutes) relieve pain in pediatric populations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eOnset of pain relief in children aged 6 years and above was determined using a pharmacokinetic/pharmacodynamic model to extrapolate data from adults who were treated with paracetamol in clinical studies. Perception of pain relief in 2- to 5-year-old children was collected via questionnaire from caregivers who had administered paracetamol to their child for pain.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePharmacokinetic/pharmacodynamic modeling generated with data from paracetamol adult pain relief studies and pharmacokinetic studies of paracetamol fast dissolving tablet and suspension demonstrated that the onset of pain relief would be reached within 30 minutes in children 6 years and above. In the 2- to 5-year-old group, 89% of parents and caregivers perceived their child felt relief from pain in less than 30 minutes after being administered paracetamol pain reliever.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eParacetamol-containing pain reliever in tablet and suspension formulations provide relief from pain in less than 30 minutes in the pediatric population.\u003c/p\u003e","manuscriptTitle":"Pain relief in children: pharmacokinetic extrapolation supported by real-world evidence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-26 18:44:10","doi":"10.21203/rs.3.rs-3835340/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f1bf1cf2-4e61-44d2-9b43-4e9141b9fe93","owner":[],"postedDate":"January 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28329392,"name":"Biological sciences/Biological techniques"},{"id":28329393,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":28329394,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2024-07-24T08:32:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-26 18:44:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3835340","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3835340","identity":"rs-3835340","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}