Tina Checchio (1), Mark Peterson (2) and Sriram Krishnaswami (3)
(1) Pharmacometrics, Global Clinical Pharmacology, Pfizer, Groton, CT, USA, (2) Pharmacometrics, Global Clinical Pharmacology, Pfizer, Cambridge, MA, USA, (3) Specialty Care, Global Clinical Pharmacology, Pfizer, Groton, CT, USA
Objectives: Estimate and summarize effects of intrinsic and extrinsic factors on tofacitinib exposure, an oral Janus kinase inhibitor, in healthy adults by pooling and analyzing individual level metrics from 16 Phase 1 trials.
Methods: Evaluable AUC and Cmax values were included from 356 healthy volunteers (HV). Taking into account the 3 hour half-life of tofacitinib, single-dose and steady-state metrics were pooled. Base model characteristics included a linear model fit to Ln(AUC) vs Ln(Dose) and a sigmoidal EMax dose function model for Ln(Cmax). Intersubject random effects were estimated on the intercept parameters of the models, and a residual error model containing a single additive term was supported. A full model approach was employed to estimate covariate effects. Covariates of interest (age, weight, race, sex, creatinine clearance (CrCL), fed/fasted status, and formulation) entered as power (continuous covariates) and fractional change (discrete covariates) functions. The possible range of exposure values for specific changes in covariates relative to the reference individual were simulated. A reference individual was defined as a healthy normal volunteer 32 year old, Caucasian, male, weighing 73 kg with baseline CrCL = 109 mL/min, receiving 5 mg tablets of tofacitinib under fasting conditions.
Results: Tofacitinib exhibited approximate dose proportional increases in AUC and Cmax over dose ranges of 0.1 to 100 mg and 0.1 to 50 mg, respectively. Differences in typical AUC were less than 20% across the range of ages, body weights, gender and races studied. Differences in typical Cmax were less than 38% across the ages, gender and races studied. Cmax decreased with increasing body weight. When administered as a solution, tofacitinib AUC and Cmax were estimated to be 15.9% (8.92-23.3%) higher and 17.4% (11.3-24.2%) higher, respectively, relative to tablet. Co-administration of tofacitinib with high fat meal resulted in 13.3% (5.43-21.7%) higher AUC and 30.3% (24.4-36.1%) lower Cmax, relative to fasted state. The model-estimated differences in formulation and food are consistent with the observed results from individual studies.
Conclusion: The magnitude of change predicted in AUC/Cmax in HV did not suggest necessary dose modification or dosing restrictions in adults based on age, body weight, gender, race, or fed status. The approach allowed use of NCA parameters to assess covariate relationships in absence of a population analysis.
Reference: PAGE 24 (2015) Abstr 3346 [www.page-meeting.org/?abstract=3346]
Poster: Methodology - Other topics