Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.

Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man.

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.

The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.

Modipafant, a new PAF antagonist: pharmacokinetics and disposition in rat, dog and man.

1. The pharmacokinetics and disposition of modipafant, a dihydropyridine PAF antagonist, were studied in rat and dog following intravenous and oral administration of the drug or its radiolabelled analogue. In addition, the pharmacokinetics were studied in man following single administration of escalating oral doses of the drug. Modipafant is a lipophilic weak base with log D(octanol) 7.4 and pKa of 4.3 and 5.3 respectively. 2. Following intravenous administration of [14C]-modipafant to rat, radioactivity is rapidly distributed throughout the body, except for the brain. A significant amount of radioactivity (probably modipafant) is rapidly distributed to the alimentary tract, particularly in the stomach. This is believed to be due to 'ion trapping' of modipafant in the acidic environment of the upper GI tract. The re-circulated modipafant may be subject to reabsorption and/or faecal excretion. 3. Following intravenous administration to rats, systemic clearance is five times greater in the male than female. The magnitude of this difference is in keeping with the clearance of other dihydropyridines such as nilvadipine. In dog, the clearance values are similar for both sexes, as expected. In this latter species, the systemic clearance decreases 6-fold with increasing dose size, indicative of saturation of a pathway of metabolism. 4. Following oral administration over a dose range of 1-12 mg/kg, modipafant is incompletely (27-67%) bioavailable in rat and dog. In the male dog, systemic exposure to drug (AUC/infinity) increased non-linearly with dose. Following oral administration to man, absorption was rapid with a mean value for Tmax of 1 h, and Cmax's ranging non-linearly from 90 to 2100 ng/ml following dosing at 12.5 to 150 mg respectively. 5. The elimination of modipafant is characterized by short half-life (mean values for t1/2 range from 1 to 3 h). However, the nature of the receptor kinetics of modipafant (slow offset) means that the drug shows a long duration of action in spite of short pharmacokinetics at pharmacologically relevant doses. 6. Following oral and intravenous administration of 14C-modipafant to rat and dog, the majority of radioactivity (mean 92%) is recovered in the faeces. The excretion of modipafant in rat and dog is characterized by metabolism, mostly to pyridine metabolites, accounting for between 38 and 75% of total clearance, the rest being cleared as unchanged drug.