Liviawati S. Wu1, Kusum Gupta1, Stefaan Rossenu2, Sushmita Chanda1, Thomas N. Kakuda1
1Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies, South San Francisco, CA, USA; 2Janssen Research and Development, Beerse, Belgium
Objectives: To develop a nonlinear pharmacokinetic (PK) model that characterizes the exposures of ALS-033719 and ALS‑033927, the active moiety and metabolite, following oral administration of a prodrug JNJ-64155806. The model was used to simulate different dosing regimens for further clinical development.
Methods: PK data were obtained from 4 phase 1 clinical studies, involving 194 healthy subjects. A total of 5767 and 5762 plasma concentrations of ALS-033719 and ALS-033927, respectively, and; 41 and 42 urine concentrations of ALS-033719 and ALS-033927, respectively, were used. Dose ranged from single dose 50-2000 mg, and twice daily 50-600 mg. The data were analyzed by a non-linear mixed effects modeling approach implemented in NONMEM V7.3.0[1]. The covariates considered were fed status, formulation, sex, race, age, weight, and selected baseline laboratory values. Although the categories of Japanese (n=6) and female (n=18) represented less than 10% of the total number of subjects, these covariates were tested because these subjects had significantly higher exposure than the rest of predominantly male subjects with other race categories. Enterohepatic circulation[2] and diurnal variation were also evaluated. Model performance was supported by diagnostic plots, standard error of parameters, evaluation of shrinkage and visual predictive checks. Dosing simulations were guided by the constraints of Cmax below 1000 ng/mL and AUC12h below 6500 ng∙h/mL.
Results: The complex JNJ-64155806 pharmacokinetics was successfully described by a two-compartment model, including pre-systemic degradation in the gut, saturable absorption from gut to intestine that has circadian variations and time-varying food effects[3], transit from intestine to central compartment, glucuronidation, and renal clearance of both parent and metabolite. The glucuronidated fraction of ALS-033719 was estimated to be 96.9%, with the remaining 3.1% eliminated in the urine. The final model included Japanese and female subjects having reduced clearance terms (30-40%), food (standard and high-fat meal) and formulation (tablet vs suspension) effects on both transit absorption rate constants and maximal rate of gastric release from gut to intestine. Inter-individual variabilities for clearance of the parent, clearance of metabolite, central volume of distribution and transit absorption rate constants were 30%, 102%, 45% and 40%, respectively; with low shrinkage of 3.4%, 16.1%, 2.4% and 4.7%, respectively. Proportional residual variabilities were estimated as 35-40% for plasma and 62-64% for urine. Simulations suggested that 100 mg loading dose followed by 50 mg twice daily will meet the Cmax and AUC criteria for the subpopulation of Japanese/women (where exposures are expected to be higher).
Conclusions: A semi-mechanistic population PK model has been developed that can adequately describe the nonlinear absorption, plasma and urine concentrations of ALS-033719 and ALS-033927 in healthy volunteers. Simulations allowed the recommendation of a dosing regimen for the clinical development of JNJ-64155806 for the indication of influenza A and B infection.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ (Eds.) NONMEM User Guides. 1989-2015. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Lehr T, Staab A, Tillmann C, Trommeshauser D, Schaefer HG, Kloft C. A quantitative enterohepatic circulation model. Clin Pharmacokinet (2009) 48(8): 529-42.
[3] Bullitta JB, Landersdorfer CB, Kinzig M, Holzgrabe U, Sorgel F. New semiphysiological absorption model to assess the pharmacodynamic profile of cefuroxime axetil using nonparametric and parametric population pharmacokinetics. Antimicrob Agents Chemother (2009) 53(8): 3462-71.
Reference: PAGE 27 (2018) Abstr 8533 [www.page-meeting.org/?abstract=8533]
Poster: Drug/Disease Modelling - Infection