Jose M. Vega

The Conduct of In Vitro and In Vivo Drug‐Drug Interaction Studies: A PhRMA Perspective

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug‐drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP‐mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug‐drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction With Fenofibrate in Humans

Simvastatin and fenofibrate are both commonly used lipid‐regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2‐period, randomized, open‐label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80‐mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160‐mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160‐mg micronized fenofibrate capsule dosed together with an 80‐mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady‐state pharmacokinetics (AUC0–24h, Cmax, and tmax) of active and total HMG‐CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady‐state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC0–24h (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG‐CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC0–24h and Cmax were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

Grapefruit juice has minimal effects on plasma concentrations of lovastatin‐derived 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors

To evaluate the effect of regular‐strength grapefruit juice, a cytochrome P4503A4 (CYP3A4) inhibitor, on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin.

Interactions between Simvastatin and Troglitazone or Pioglitazone in Healthy Subjects

Two randomized, two‐period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG‐CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once‐daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once‐daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once‐daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration‐time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG‐CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by ∼30% for Cmax and ∼40% for AUC), but time to reach Cmax(tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (∼25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG‐CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug‐metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

Image-derived input function for [11C]flumazenil kinetic analysis in human brain

PURPOSE We describe a method for analysis of [11C]flumazenil data using an input curve directly derived from the positron emission tomography (PET) images. PROCEDURE The shape of the tracer plasma curve was obtained from the product of the intact flumazenil fraction in plasma in six arterial samples and the internal carotid artery time-activity curve (TAC). The resulting curve was calibrated using the [11C]flumazenil concentration in three of the six samples. The curve peak was recovered by adding an exponential function to the scaled curve whose parameters were estimated from simultaneous fittings of several tissue TACs assuming that all regions share the same input. RESULTS Good agreement was found between the image-derived and the experimental plasma curves in six subjects. Distribution volumes were highly correlated with linear regression slope and intercept values between [0.94, 1.03] and [-0.10, 0.16], respectively. CONCLUSION The proposed method is suitable for benzodiazepine receptor quantification requiring only a few blood samples.

Simvastatin Does Not Affect CYP3A Activity, Quantified by the Erythromycin Breath Test and Oral Midazolam Pharmacokinetics, in Healthy Male Subjects

Potential for inhibition of CYP3A activity by simvastatin, an HMG‐CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 μCi [14C N‐methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once‐daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1′‐hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

METABOLISM AND DISPOSITION OF A POTENT AND SELECTIVE GABA-Aα2/3 RECEPTOR AGONIST IN HEALTHY MALE VOLUNTEERS

[14C]7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine ([14C]-TPA023; 99 μCi/dose) was administered to five young, healthy, fasted male subjects as a single oral dose (3.0 mg) in solution (propylene glycol/water, 10:90 v/v). The parent compound was rapidly absorbed (plasma Tmax ∼2 h), exhibited an apparent terminal half-life of 6.7 h, and accounted for approximately 53% of the total radioactivity in plasma. After 7 days of collection, the mean total recovery of radioactivity in the excreta was 82.6%, with 53.2% and 29.4% in urine and feces, respectively. Radiochromatographic analysis of the excreta revealed that TPA023 was metabolized extensively, and only trace amounts of unchanged parent were recovered. Radiochromatograms of urine and feces showed that TPA023 underwent metabolism via three pathways (t-butyl hydroxylation, N-deethylation, and direct N-glucuronidation). The products of t-butyl hydroxylation and N-deethylation, together with their corresponding secondary metabolites, accounted for the majority of the radioactivity in the excreta. In addition, approximately 10.3% of the dose was recovered in urine as the triazolo-pyridazine N1-glucuronide of TPA023. The t-butyl hydroxy and N-desethyl metabolites of TPA023, the TPA023 N1-glucuronide, and the triazolo-pyridazine N1-glucuronide of N-desethyl TPA023 were present in plasma. In healthy male subjects, therefore, TPA023 is well absorbed and is metabolized extensively (t-butyl hydroxylation and N-deethylation > glucuronidation), and the metabolites are excreted in urine and feces.

Grapefruit juice (GFJ) has a small effect on lovastatin plasma HMG‐CoA reductase inhibitor (HMGRI) profiles

Clinical Pharmacology & Therapeutics (1999) 65, 149–149; doi: