James F. McLeod

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.

“Cocktail” Approaches and Strategies in Drug Development: Valuable Tool or Flawed Science?

There is an increasing interest in the simultaneous administration of several probe substrates to characterize the activity of multiple drug‐metabolizing enzymes, the so‐called “cocktail” approach. However, this method remains controversial and is being investigated more extensively. No general consensus has emerged on the applicability of this approach in clinical investigation and during drug development. The objective of the article is to review this important yet specialized technique, as well as its merits, drawbacks, and potential application in drug development. Among the two‐, three‐, four‐, five‐, and six‐drug in vivo cocktails previously evaluated in humans, a variety of substrate probe combinations have been studied. Some probe combinations have been validated not to interact in vivo and have been useful in characterizing drug‐drug interaction potential and metabolic enzyme induction in humans. For drug candidates that affect two or more in vitro pathways or are potential gene inducers, the use of a cocktail approach may facilitate the rapid delineation of the drug candidates drug interaction potential. It may also offer the potential of providing clear guidance on safely conducting larger clinical studies and limiting comedication restrictions to only those likely to be clinically relevant.

The effect of food on the oral bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects

Nateglinide (Starlix®, SDZ DJN 608 or A‐4166), a new insulinotropic agent, is intended to be administered prior to a meal in order to improve early insulin release in non‐insulin‐dependent diabetes mellitus patients. The effects of a meal on the oral bioavailability and pharmacodynamic actions of nateglinide were investigated. Twelve healthy male subjects completed this randomized, single‐dose, four‐way crossover study in which each subject received a 60 mg dose of nateglinide 10 minutes before the start of and immediately after a high‐fat breakfast meal. In addition, each subject received a single 30 and 60 mg dose of nateglinide under fasting conditions. Plasma and urine concentrations of nateglinide were determined by an HPLC method while plasma glucose and insulin concentrations were measured by standard immunoassay methods. Compared to the fasted state, administration of nateglinide 10 minutes before the meal was associated with an increase in the rate of absorption (12% increase in Cmax and 52% decrease in tmax), while there was no significant effect on the extent of absorption (AUC). Alternatively, when nateglinide was given after the meal, a food effect was observed that was characterized by a decrease in the rate of absorption: 34% decrease in Cmax and a 22% increase in tmax but no significant effect on AUC. Nateglinide was rapidly eliminated with plasma t1/2 = 1.4 hours. Its plasma renal clearance, 20.7 ml/min, appears to be due mostly to active tubular secretion. However, only 13% to 14% of the dose is recovered as nateglinide in the urine. The 30 and 60 mg tablets were dose proportional in terms of both AUC and Cmax; both tmax and t1/2 were dose independent. Regardless of timing, the combination of a meal and nateglinide produced a larger increase in insulin levels than did nateglinide alone. Meal‐related glucose excursions were eliminated when nateglinide was taken prior to the meal. Thus, the rapid onset/short duration stimulation of insulin release by nateglinide should allow good control of prandial hyperglycemia while limiting exposure to hyperinsulinemia.

Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis

This single‐dose, open‐label, parallel‐group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis ande matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half‐lives were comparable. Mean ± SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 ± 4.9 vs. 5.6 ± 1.3 μg/ml; AUC(0‐t), 18.5 ± 7.5 vs. 14.2 ± 2.1 μg·h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein‐bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.

Effect of Meal Timing Not Critical for the Pharmacokinetics of Tegaserod (HTF 919)

This study assessed the pharmacokinetic profiles of administering tegaserod (HTF 919) at different time intervals with respect to a meal. It was a randomized, open‐label, two‐phase, five‐period crossover study. In the first phase, 18 healthy subjects received a single 12 mg oral dose of tegaserod administered either 30 or 15 minutes prior to the start of the 600‐calorie, fat‐rich breakfast. In the second phase, subjects received a single 12 mg oral dose of tegaserod 1 minute before, 2.5 hours after the start of meal, or with a continued 4‐hour postdose fast. Safety assessment and plasma samples for the determination of drug concentration were obtained for 24 hours postdose. Noncompartmental analysis results indicated that the AUC of tegaserod was reduced by almost half under fed conditions compared to the fasted condition. Exploratory analyses were implemented to further investigate the absorption characteristics of tegaserod under different fed conditions. A numerical deconvolution approach was used to obtain the tegaserod oral absorption versus time profiles under both fasted and fed conditions. The tegaserod oral absorption versus time profiles were then fitted by NONMEM to a model containing two absorption phases. Based on the absorption analyses, we found that the reduction in the bioavailability of tegaserod under fed conditions was primarily due to a decrease in the extent of absorption and less so to a decrease in the absorption rate(s). Therefore, although the timing of administration of food does not appear to significantly alter the pharmacokinetics of tegaserod, the administration of food reduces the AUC by approximately 50%.

Pharmacokinetics of nateglinide in renally impaired diabetic patients.

Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open‐label, single‐dose, two‐center study included patients (mean age = 57 ± 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age‐, sex‐, height‐, and weight‐matched healthy controls (n = 20). All participants received a single 120‐mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0‐t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9–2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.

Effects of Oral Posaconazole on the Pharmacokinetics of Atazanavir Alone and With Ritonavir or With Efavirenz in Healthy Adult Volunteers

Background:Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated. Methods:A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers. Results:Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively. Conclusions:Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.

The pharmacokinetics of the novel promotile drug, tegaserod, are similar in healthy subjects : male and female, elderly and young

Tegaserod (HTF 919) is a selective 5‐HT4 receptor partial agonist in development for the treatment of irritable bowel syndrome.

Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus.

AbstractObjectives: Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus. Methods: Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack. Results: Taken 10 min before meals, doses of 30–120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters. Conclusions: Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia.

Pharmacokinetics of multiple doses of valsartan in patients with heart failure.

Angiotensin II has adverse actions in heart failure including vasoconstriction, aldosterone secretion, and activation of the sympathetic nervous system. Valsartan, a potent specific angiotensin II type 1 receptor blocker, may produce beneficial effects in heart failure. The purpose of this study was to evaluate the steady-state pharmacokinetics of valsartan 40, 80, and 160 mg each given every 12 h for 7 days in heart failure patients. Eighteen patients with chronic stable heart failure and left ventricular ejection fractions ≤ 40% received each dosing regimen starting with the 40-mg dose. On day 7 of each dosing period, serial blood samples were obtained over 12 h for pharmacokinetic assessment. Results showed that the mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased in a linear and nearly proportional manner with valsartan dose. A dose-proportionality assessment, based on a statistical power model, showed that doubling the dose increased the AUC and Cmax 1.8 times. The pharmacokinetics of valsartan are predictable in heart failure patients within the dose range of 40–160 mg BID. Age did not appear to have influenced the valsartan clearance in heart failure patients. The pharmacokinetic values were higher in heart failure patients than in healthy volunteers. All doses were generally safe and well tolerated.