Amlodipine, Valsartan and Hydrochlorothiazide (Page 6 of 9)
Amlodipine, Valsartan and Hydrochlorothiazide
Following oral administration of amlodipine, valsartan and hydrochlorothiazide in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and HCTZ are reached in about 6 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and HCTZ from amlodipine, valsartan and hydrochlorothiazide tablets are the same as when administered as individual dosage forms.
The bioavailability of amlodipine, valsartan, and HCTZ were not altered when amlodipine, valsartan, and hydrochlorothiazide tablets were administered with food. Amlodipine, valsartan and hydrochlorothiazide may be administered with or without food.
Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. Absolute bioavailability is about 25% (range 10% to 35%).
The steady state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Valsartan shows biexponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP450 enzymes indicated that the CYP2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP450 isozymes at clinically relevant concentrations. CYP450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax ) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.
Hydrochlorothiazide binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline biexponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.
About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.
Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life, and AUC. Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. Limited amount of data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Pharmacokinetics of valsartan do not differ significantly between males and females.
Pharmacokinetic differences due to race have not been studied.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Valsartan has not been studied in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis.
In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30 <CrCl <90 mL/min) and tripled in severe renal impairment (CrCl ≤30 mL/min), compared to individuals with normal renal function (CrCl> 90 mL/min) [see USE IN SPECIFIC POPULATIONS (8.6) ].
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%. On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight) [see USE IN SPECIFIC POPULATIONS (8.7) ].
In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Impact of other drugs on amlodipine
Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.
Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see DRUG INTERACTIONS (7) ].
Impact of amlodipine on other drugs
Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see DRUG INTERACTIONS (7) ].
A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see DRUG INTERACTIONS (7) ].
A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see DRUG INTERACTIONS (7) ].
Drugs that alter gastrointestinal motility
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.
In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 hours before cholestyramine resulted in 35% reduction in exposure to hydrochlorothiazide.
Antineoplastic agents (e.g., cyclophosphamide, methotrexate)
Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Alcohol, barbiturates, or narcotics
Potentiation of orthostatic hypotension may occur.
Skeletal muscle relaxants
Possible increased responsiveness to muscle relaxants such as curare derivatives.
Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.
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