Organ Impairment-Drug-Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs.

The organ impairment and drug-drug interaction (OI-DDI) database is the first rigorously assembled database of pharmacokinetic drug exposure data from publicly available renal and hepatic impairment studies presented together with the maximum change in drug exposure from drug interaction inhibition studies. The database was used to conduct a systematic comparison of the effect of renal/hepatic impairment and pharmacologic inhibition on drug exposure. Additional applications are feasible with the public availability of this database.

Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.

Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate.

Prediction of maximum exposure in poor metabolizers following inhibition of nonpolymorphic pathways.

Marked increases in exposure of some substrates have been noted in poor metabolizers given inhibitors of nonpolymorphic enzymes. Among the small number of clinical trials conducted to investigate this problem, a wide variation in the degree of maximum exposure ratios (area under the curve in poor metabolizers in the presence of inhibitor/area under the curve in extensive metabolizers) among the different substrates has been reported, with some trials reporting profound increases (> tenfold), and others demonstrating less remarkable changes (< twofold). The conduct of such trials raises safety concerns for the trial participants, in addition to other ethical and logistic concerns; therefore, the possibility was investigated that maximum exposure (area under the curve in poor metabolizers in the presence of an inhibitor) could be predicted, and that substrates susceptible to large increases in exposure could be identified. Existing clinical trials were identified by data mining the literature. A theoretical approach was developed to predict maximum exposure in poor metabolizers from studies in extensive metabolizers treated with an inhibitor of the nonpolymorphic pathway. Maximum exposure was predicted in eleven instances and the mean percentage difference between predicted and observed was 11.9%. Substrates with a fraction of substrate dose metabolized by the polymorphic enzyme (fm(POLY)) higher than 75% are at greater risk of exhibiting maximum exposure ratios of more than tenfold.

Relationship between extent of inhibition and inhibitor dose: literature evaluation based on the metabolism and transport drug interaction database.

A comprehensive search of the literature was undertaken using the Metabolism and Transport Drug Interaction Database (http://depts.washington.edu/didbase/) to evaluate the relationship between extent of inhibition and inhibitor dose. The search included reversible and irreversible inhibitors in studies conducted in the period 1966-2003. Only twelve inhibitors met the criterion of the search: study population exposed to more than one dose of inhibitor within a given study design. Six were reversible inhibitors: ciprofloxacin, enoxacin, felbamate, fluconazole, fluvoxamine and ketoconazole. The other six (cimetidine, diltiazem, disulfiram, paroxetine, verapamil and ritonavir) are considered irreversible inhibitors. Most of the AUC/Clearance data available for both types of inhibitors suggested evidence of dose-dependent inhibition. In the case of reversible inhibitors, the evidence of dose-dependent inhibition is consistent with a number of recent studies suggesting the determination of in vivo inhibition constants based on plasma concentration of inhibitor.

Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin.

The objective of this study was to determine if repeated administration of levetiracetam alters the pharmacokinetics or the pharmacodynamics of warfarin. Forty-two healthy subjects (18-50 years old) were recruited into the study. After a dose-finding phase and a stabilization phase, during which a warfarin treatment was introduced and the dose maintained stable for at least 5 days, 18 male and 8 female subjects were eligible and enrolled. Subjects received warfarin (2.5, 5 or 7.5 mg/day) plus levetiracetam 1000 mg bid, and warfarin plus placebo. The treatment periods were 7 days long and were separated by a 3-day wash-out period. The protein binding and the pharmacokinetic profiles of R- and S-warfarin were assessed at steady state by analysis of blood samples, and the anticoagulant effect was measured using the international normalized ratio (INR). The ratios of the geometric means for AUC(ss) (90% confidence interval) between coadministration of warfarin with levetiracetam or with placebo were 97.17% (92.85%, 101.68%) for R-warfarin and 100.16% (96.43%, 104.02%) for S-warfarin. Results for C(max), C(min) and oral clearance were consistent with those of AUC(ss). In addition, the protein binding of warfarin was not affected by the concomitant treatment. The INR values measured the last 5 days of each period were not statistically altered by the concomitant administration of levetiracetam or placebo: 1.59+/-0.18 for warfarin alone, 1.49+/-0.21 when coadministered with placebo, and 1.55+/-0.23 with levetiracetam (means+/-S.D.). The frequency and profile of adverse events under the concomitant therapy of warfarin and levetiracetam were expected for subjects receiving these drugs, and the coadministration was safe. Moreover, levetiracetam pharmacokinetics after repeated warfarin administration did not differ from those previously reported in healthy volunteers. At the doses administered, there is no evidence of a pharmacokinetic or pharmacodynamic interaction between warfarin and levetiracetam.

Repeated administration of the novel antiepileptic agent levetiracetam does not alter digoxin pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVE: This study was undertaken to determine whether levetiracetam (Keppra) affected the pharmacokinetic or pharmacodynamic profile of digoxin in healthy adults. METHODS: Seven men and four women (19-48 years old) completed this double-blind, placebo-controlled study. Each received digoxin 0.25 mg once daily (0.5 mg on day 1) during the 1-week run-in period, followed by two 1-week periods of coadministration of digoxin with levetiracetam (2000 mg/day) or placebo in a two-way crossover design. The pharmacokinetics of digoxin and levetiracetam were assessed by analysis of blood samples. ECG recordings were taken to monitor effects of levetiracetam on digoxin pharmacodynamics. RESULTS: The ratios of geometric means, using a 90% confidence interval, between coadministration of digoxin with levetiracetam or placebo were 103.96% (99.18%, 108.95%) for AUC(ss), 100.87% (89.52%, 113.66%) for C(max), 97.67% (82.76%, 115.26%) for PTF, and 99.04% (90.98%, 109.00%) for C(min). Although digoxin produced predictable changes in ECG, its pharmacodynamic parameters did not differ significantly between levetiracetam and placebo administration. Furthermore, the pharmacokinetics of levetiracetam were not altered in the presence of digoxin. Co-administration of levetiracetam and digoxin was well tolerated. CONCLUSION: At the doses administered, there was no pharmacokinetic interaction and no evidence of a pharmacodynamic interaction between digoxin and levetiracetam.