Assessing the adequacy of a minimal PK sampling schedule for individual dose adjustment decisions in a proof of mechanism (PoM) study in a special population
Franziska Schaedeli Stark and Norman Mazer
Roche Pharmaceutical Research and Early Development, Clinical Development, Roche Innovation Center Basel, Switzerland
Objectives: Drug A was previously tested in healthy subjects and patients and is now being investigated in a proof of mechanism (PoM) study for a new indication in a special population with potentially different PK characteristics. Individual dose increases may be required to reach the minimum efficacious exposure (AUCss) for the PoM. The objectives of this work are (i) to propose a minimal PK sampling schedule for making an early individual dose increase decision and (ii) to demonstrate how adequate the decisions will be if CL is up to two-fold different in the special population.
Methods: The PoM study design includes a 3-step dose-escalation phase over 6 weeks to reach the minimum efficacious steady-state exposure that will be maintained from weeks 7 to 17. AUCss prediction and subsequent dose decision (at week 7) will be based on PK samples collected during the dose escalation phase. Prior PK information on drug A in healthy subjects and patients demonstrated linearity over the PoM dose range and was described by a two-compartment model. An optimized and robust PK sampling schedule for empirical Bayes estimates (EBEs) of individual PK parameters was derived from evaluations with PFIM 4.0 [1,2]. Simulations were performed using NONMEM to assess how much this sampling schedule could be further reduced without compromising the decision on a dose increase.
Results: A total of 10 samples per individual up to day 29 yielded PFIM estimates for RSE that were 6% for CL and less than 30% on all other PK parameters; shrinkage was 3%, 10% and 29% on CL, V2 and V3, respectively. Simulations demonstrated accurate dose increase decisions with PK sampling up to day 15, even though EBEs for CL (and AUCss) were less precise and possibly less accurate (especially in the upper range of exposure). With 5 PK samples (day 1: 2 and 12h; day 2: pre-dose; day 15: pre-dose and 3h) the risk of missing a true underexposure was less than 5% in all scenarios.
Conclusions: A minimal PK sampling schedule was shown to facilitate adequate and timely dose decisions to ensure sufficient individual exposure in the PoM study even if the true CL in the new population was two-fold different from the prior value. The additional samples recommended by PFIM for precise and accurate PK characterization may be collected later in the study.
References:
[1] Retout S, Duffull S, Mentré F (2001) Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs. Comput Methods Programs Biomed 65: 141–151.
[2] Combes FP, Retout S, Frey N, Mentré F (2013) Prediction of shrinkage of individual parameters using the bayesian information matrix in nonlinear mixed effect models with evaluation in pharmacokinetics. Pharm Res 30: 2355–2367. doi:10.1007/s11095-013-1079-3.
