###  Trandolapril and Verapamil Hydrochloride Extended-Release Tablets

Following a single oral dose of trandolapril and verapamil hydrochloride extended-release tablets in healthy subjects, peak plasma concentrations are reached within 0.5 to 2 hours for trandolapril and within 4 to 15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5 to 15 hours. Cleavage of the ester group converts trandolapril to its active diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2 to 12 hours. The pharmacokinetics of trandolapril and trandolaprilat are not altered when trandolapril is administered in combination with verapamil, compared to monotherapy.

The AUC and Cmax for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg trandolapril. The increase in Cmax is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Administration of trandolapril and verapamil hydrochloride extended-release tablets 4 mg/240 mg (4 mg trandolapril and 240 mg verapamil hydrochloride extended-release) with a high-fat meal does not alter the bioavailability of trandolapril whereas verapamil peak concentrations and area under the curve (AUC) decrease 37% and 28%, respectively. Food thus decreases verapamil bioavailability and the time to peak plasma concentration for both verapamil and norverapamil are delayed by approximately 7 hours. Both optical isomers of verapamil are similarly affected.

The elimination half-life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing binding to plasma and tissue ACE.

The terminal half-life of verapamil is 6 to 11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of trandolapril and verapamil hydrochloride extended-release tablets. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral trandolapril and verapamil hydrochloride extended-release tablets dose. 

The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (≥65 years) than in younger subjects. The bioavailability of verapamil and norverapamil are increased by 87% and 77%, respectively, and that of trandolapril by approximately 35% in the elderly. AUCs are approximately 80% and 35% higher, respectively. 

Verapamil Component

With the immediate release formulation, more than 90% of the orally administered dose is absorbed with peak plasma concentrations of verapamil observed 1 to 2 hours after dosing. A delayed rate but similar extent of absorption is observed for the sustained release formulation when compared to the immediate release formulation. Because of the rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20% to 35%. A nonlinear correlation exists between verapamil dose and plasma concentrations.

In early dose titration with verapamil, a relationship exists between plasma concentrations of verapamil and prolongation of the PR interval. However, during chronic administration, this relationship may disappear. No relationship has been established between the plasma concentration of verapamil and reduction in blood pressure. 

In healthy subjects, orally administered verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Urinary excretion of unchanged drug is about 3% to 4% of the dose. Verapamil is approximately 90% bound to plasma proteins. 

In patients with hepatic insufficiency, verapamil clearance is decreased about 30% and the elimination half-life is prolonged up to 14 to 16 hours (see PRECAUTIONS). In patients with liver dysfunction, a dosage adjustment may be required. In the elderly (≥65 years), verapamil clearance is reduced resulting in increases in elimination half-life.

Trandolapril Component

Following oral administration of trandolapril, the absolute bioavailability of trandolapril is approximately 10% as trandolapril and 70% as trandolaprilat. Plasma concentrations of trandolaprilat but not trandolapril increase in proportion with dose. Plasma concentrations of trandolaprilat decline in a triphasic manner. The more prolonged terminal elimination phase probably represents a small fraction of dose saturably bound to ACE. 

After an oral radiolabeled dose of trandolapril, excretion of trandolapril and metabolites account for 33% of the dose in the urine and about 66% in the feces. Less than 1% of the dose is excreted in the urine as unchanged drug. Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration. 

Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients (see DOSAGE AND ADMINISTRATION).

Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION).