Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the influence of dosing regimens

Abstract

Patient compliance is better with formulations that require less frequent dosing than with formulations that require more frequent dosing. Intramuscular risperidone and long-acting oxybutynin are two examples of medicines reformulated for less frequent dosing. However, it is not clear whether better compliance with less frequent dosing regimens translates to improved therapeutic outcome. At equivalent daily doses and typical patterns of compliance, fortnightly intramuscular depot administrations of risperidone provide better pharmacokinetic coverage than once-daily oral dosing. Once-daily dosing of oxybutynin is no better at maintaining pharmacokinetic exposure than twice-daily dosing at half strength. The use of simulated compliance data as input to pharmacokinetic models is useful to assess the impact of noncompliance on internal drug exposure. To determine whether, for oxybutynin and risperidone, drug exposure is better with less frequent dosing regimens than with regimens that require more frequent dosing. Pharmacokinetic models of oxybutynin (5 mg twice-daily and 10 mg once-daily) and risperidone (2 mg once-daily orally and 25 mg fortnightly intramuscular injection) were developed. Simulations of multiple doses were performed by use of stochastic models of dose-taking compliance and clinic visit attendance. At therapeutic concentrations and with typical patterns of noncompliance, intramuscular injections of risperidone resulted in a 41% (SD 12%) greater pharmacokinetic coverage than the oral dose, 76% (SD 10%) vs. 35% (SD 7%). No discernable differences were evident between once- and twice-daily formulations of oxybutynin, 29.2% (SD 10%) vs. 29.0% (SD 13%). For equivalent doses for each drug, the longer acting preparation of risperidone, but not oxybutynin, is pharmacokinetically more forgiving of noncompliance than the shorter acting counterparts. Further analysis is required to confirm whether these observations are valid clinically.