58 Clinical Pharmacokinetics and Pharmacodynamics of Chemokine Inhibitors: Implications for Rational Dosing Craig W Hendrix Bloomberg Sch of Publ Hlth, John Hopkins Univ, Baltimore, MD, USA

Rational Dosing. Rational dosing of drugs is best informed by an understanding of both the pharmacokinetics of the drug (concentration-time relationship) as well as the pharmacodynamics of the drug (exposure-response relationship). Armed with an understanding of drug exposure levels which achieve desired efficacy and avoid undesired toxicity combined with the knowledge of how drug concentration changes over time, one can build a useful dose-exposure-response model. This model enhances the ability to rationally choose a dosing regimen that achieves the optimal balance of antiviral effect with minimized toxicity.

Traditional Antiretroviral Characteristics. During the development of currently marketed antiretroviral drugs, the pharmacodynamic relationship between antiretroviral effect and drug exposure (trough, peak, area under the concentration – time curve, inhibitory quotient) were usually discovered, if at all, well after the marketing of the drug. In some cases, especially for nucleoside analogs with complicated intracellular pharmacokinetics like zidovudine, this has led to the adoption of more rational dosing regimens with improved adherence and reduced toxicity without sacrificing efficacy.  Additionally, where it has been determined, trough concentrations relative to viral sensitivity to the drug (inhibitory quotient, Cmin/IC₅₀) are often the drug exposure variable that best correlates with antiviral effect.

Chemokine Inhibitor Differences. Chemokine inhibitors appear to differ from previously developed ARV classes in several important ways. In some cases their biologic effect is not best correlated with trough concentrations.  For several, there exists a prolonged period of antiviral effect well after the drug is cleared from the blood. These findings suggest that dosing amount and frequency should not be based simply on drug half-life alone. While the mechanism for the apparent differences between chemokine inhibitors and other ARV classes remains unclear, our understanding of the relationship between drug exposure and biologic effect are emerging sufficiently early in clinical development that this PK-PD knowledge about chemokine inhibitors can inform useful dose-concentration-response models which enable a more rational choice of dosing regimens to be incorporated into definitive phase 3 clinical studies.