Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies
Background and Objectives
Prediction of human pharmacokinetics for monoclonal antibodies (mAbs) plays an important role for first-in-human (FIH) dose selection. This retrospective analysis compares observed FIH pharmacokinetic data for 16 mAbs to those predicted in humans based on allometric scaling of Cynomolgus monkey pharmacokinetic data.
Ten mAbs exhibited linear pharmacokinetics in monkeys based on non-compartmental analysis. For these, simple allometric scaling based on bodyweight was applied to predict human clearance (CL) and volume of distribution (Vd) from those obtained in monkeys. Six mAbs exhibited nonlinear pharmacokinetics in monkeys based on population modelling. For these, a population modelling approach using nonlinear mixed-effects modelling software, NONMEM®, was applied to describe monkey data by a two-compartment pharmacokinetic model with parallel linear and nonlinear elimination from the central compartment. The pharmacokinetic parameters in monkeys were then scaled to humans based on simple allometry. Human concentrationtime profiles of these mAbs were then simulated and compared with those observed in the FIH studies.
Antibodies with linear elimination in monkeys also exhibited linear elimination in humans. For these, observed CL and Vd were predicted within 2.3-fold by allometry. The predictability of human peak serum concentration (Cmax) and area under the serum concentration-time curve (AUC) for mAbs with nonlinear pharmacokinetics in monkeys was, however, concentration dependent. Cmax was consistently overestimated (up to 5.3-fold higher) when below the predicted Michaelis-Menten constant (Km; range 0.3–4 μg/mL). The prediction of human Cmax was within 2.3-fold when concentrations greatly exceeded Km. Similarly, differences between predicted human AUCs and those observed in the FIH studies were much greater at low doses/concentrations. Consequently, predicted drug exposure in humans at low starting doses (range 0.01–0.3 mg/kg) in FIH studies was poorly estimated for three of six mAbs with nonlinear pharmacokinetics.
Allometric prediction of human pharmacokinetics may be sufficient for mAbs that exhibit linear pharmacokinetics. For mAbs that exhibited nonlinear pharmacokinetics, the best predictive performance was obtained after doses that achieved target-saturating concentrations.
KeywordsUstekinumab Allometric Scaling Linear Pharmacokinetic Nonlinear Pharmacokinetic Human Pharmacokinetic
No source of funding was used to assist in the preparation of this manuscript. The authors wish to thank Dr Marc Gastonguay for insightful technical discussion and Dr Donald Mager for critical review of the manuscript. All authors are employees of Amgen and own Amgen shares. The authors have no other conflicts of interest that are directly relevant to the content of this study.
- 1.Meibohm The role of pharmacokinetics and pharmacodynamics in the development of biotech drugs. In: Meibohm B, editor. Pharmacokinetics and pharmacodynamics of biotech drugs: principles and case studies in drug development. Weinheim: Wiley-VCH, 2006: 3–12Google Scholar
- 5.Center for Drug Evaluation and Research, US FDA. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville (MD): FDA, 2005 Jul [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf [Accessed 2010 Nov 9]
- 6.Committee for Medicinal Products for Human Use, European Medicines Agency. Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with investigational medicinal products. London: European Medicines Agency, 2007 Jul 19 [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf [Accessed 2010 Nov 9]
- 19.Boxenbaum H, D’Souza RW. Interspecies pharmacokinetic scaling, biological design, and neoteny. In: Testa B, editor. Advances in drug research. London: Academic Press Limited, 1990: 139–96Google Scholar
- 20.Chappell WR, Mordenti J. Extrapolation of toxicological and pharmacological data from animals to humans. In: Testa B, editor. Advances in drug research. San Diego (CA): Academic Press, 1991: 1–116Google Scholar
- 31.US FDA. Drug approval package: Avastin (bevacizumab). Summary basis of approval [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/STN-125085_Avastin.cfm [Accessed 2010 Nov 26]
- 34.US FDA. Infliximab product approval information — licensing action: Remicade. Summary basis of approval [online]. Available from URL: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm093327.htm [Accessed 2010 Nov 26]
- 35.US FDA. Overview: Rituxan (rituximab). Summary basis of approval [online]. Available from URL: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=RITUXAN&CFID=51165734&CFTOKEN=c8cf74698099620-6129AB8A-B4E8-AA2F-738FF37B5F9776F9 [Accessed 2010 Nov 26]
- 37.IVIG HCA pharmacy protocol [online]. Available from URL: http://www.docstoc.com/docs/19660410/IVIG-PHARMACY-PROTOCOL [Accessed 2010 Dec 3]
- 41.US FDA. Trastuzumab product approval information — licensing action 9/25/98: Herceptin. Summary basis of approval [online]. Available from URL: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/ApprovalApplications/TherapeuticBiologicAp plications/ucm080591.htm [Accessed 2010 Nov 26]
- 42.US FDA. Drug approval package: Mylotarg (gemtuzumab ozogamicin) injection. Summary basis of approval [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21174_Mylotorg.cfm [Accessed 2010 Nov 26]
- 43.US FDA. Drug approval package: Vectibix panitumumab injectable. Summary basis of approval [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125147s0000TOC.cfm [Accessed 2010 Nov 26]