The Clinically Relevant Half Life in Pharmacokinetics & Pharmacodynamics

Author(s): Grover, Anita | Advisor(s): Benet, Leslie Z. | Abstract: For the rare drug that exhibits a single half life in its elimination and is dosed via intravenous bolus, predictability in plasma concentration fluctuation and accumulation based on half life led to the association between dosing interval and half life. The overwhelming majority of drugs, however, follow multi-exponential kinetics and are dosed orally, leading to multiple half lives that describe the behavior of the drug. Current initial dosing recommendations are often guided by the terminal pharmacokinetic half life (t1/2,β) under the assumption that this slowest phase in disposition will predict drug behavior in the body. By blending modeling a simulation techniques with a clinical pharmacology understanding, we here aim to develop a unique perspective on the clinically relevant half life in pharmacokinetics and pharmacodynamics, including the relevance of t1/2,β during multiple dosing. We examine cases in which the functioning of drug transporters is altered by a drug-drug interaction or genetic polymorphism and show the resulting change in distribution volume can lead to a change in drug effect or toxicity, as well as a change in half life independent of a change in clearance. We also further define and advance applications of the operational multiple dosing half lives (t1/2,op). Using Monte Carlo simulation, our results predict a way to maximize t1/2,op relative to t1/2,β by using an absorption rate constant close to the terminal elimination rate constant in formulation design. In this way, drugs that may otherwise be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times t1/2,β, maximizing compliance, while maintaining tight plasma accumulation and fluctuation. We present a tacrolimus population pharmacokinetic analysis of Native American patients, further exemplifying the utility of t1/2,op. Finally, as there is currently no unifying relationship between drugs' pharmacokinetics and pharmacodynamic measures of clinical benefit and toxicity, we present pharmacodynamic considerations based on a continuum between direct and indirect pharmacokinetic-pharmacodynamic models. Prior to intensive modeling efforts during drug development, this framework may be used to inform clinical trial and formulation design using data from relatively few patients early in clinical trials.