Dealing with Autoinhibition of Drug Clearance in Early Clinical Product Development
Iñaki F. Trocóniz*, Ilonka Zsolt**, María J. Garrido*, Marta Valle**, and Manel J. Barbanoj**
*, Departamento de Farmacia y Tecnología Farmacéutica. Facultad de Farmacia. Universidad de Navarra (Pamplona, Spain) **, Centre d Investigació de Medicaments. Institut de Recerca de l HSCSP. Department de Farmacología i Terapéutica. UAB (Barcelona, Spain)Complexities related with drug clearance such as drug-drug interactions, autoinhibition/induction, genetic polymorphism, dose-dependency, etc, are major issues that sometimes can result in the stop of the development process. In the current study, a new compound with adequate efficacy, tolerability and pharmacokinetic profiles in the 6-1200 mg dose range after single oral administration, showed a clear decrease in clearance after multiple oral administration of 240, 350 or 500 mg to 24 healthy volunteers randomly distributed in three dose groups. The design was as follows: One week after the first administration, six additional doses were given once dialy, therefore the duration of the study was two weeks and a total of 33 blood samples were obtained in each individual for pharmacokinetic evaluation. In this kind of situation the question regarding the ability of the drug to inhibit completely its own metabolism is a critical issue since in such a case the drug would accumulate indefinitely in the body. This point was addressed by population pharmacokinetic modelling since graphic exploration of raw data showed that after the last dose the steady-state was not achieved. Drug absorption and drug distribution were described with a first order process and a one compartment model, respectively. Autoinhibition in clearance was modelled using a feedback model where the plasma drug concentrations inhibited the turnover rate of the elimination (enzymatic) activity in an EMAX manner. The model finally selected, which was internally and externally validated, gave an estimate of maximum degree of clearance inhibition close to 95 %. The possibility of having a reasonable (practical) dose regimen on the basis of the described pharmacokinetic behaviour was explored by computer simulations using the model selected and its parameter estimates together with pharmacodynamic information obtained from previous phase I studies. It was shown that oral doses of 120 mg given once daily, with the additional support of one extra 120 mg dose during the first two days of treatment, resulted in adequate drug exposure profiles reaching the steady-state one week after the start of the treatment.