Amlodipine Besylate and Atorvastatin Calcium (Page 7 of 13)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amlodipine besylate and atorvastatin calcium is a combination of two drugs, a dihydropyridine calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor (atorvastatin). The amlodipine component of amlodipine besylate and atorvastatin calcium inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine besylate and atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Amlodipine

Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal’s or variant) angina.

Atorvastatin

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.

12.2 Pharmacodynamics

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Atorvastatin

Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].

Drug interactions

Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)].

12.3 Pharmacokinetics

Absorption

Amlodipine: After oral administration of therapeutic doses of amlodipine alone, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%.

Atorvastatin: After oral administration alone, atorvastatin is rapidly absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for C_max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].

Amlodipine besylate and atorvastatin calcium: Following oral administration of amlodipine besylate and atorvastatin calcium, peak plasma concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine besylate and atorvastatin calcium are not significantly different from the bioavailability of amlodipine and atorvastatin administered separately (see above).

The bioavailability of amlodipine from amlodipine besylate and atorvastatin calcium was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from amlodipine besylate and atorvastatin calcium by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.

Distribution

Amlodipine: Ex vivo studies have shown that approximately 93% of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Atorvastatin: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.3)].

Metabolism

Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism.

Atorvastatin: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P4503A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent amlodipine compound and 60% of the metabolites of amlodipine are excreted in the urine.

Atorvastatin: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours because of the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Specific Populations

Geriatric

Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose of amlodipine may be required.

Atorvastatin: Plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of atorvastatin in the elderly population compared to younger adults [see Use in Specific Populations (8.5)].

Pediatric

Amlodipine: Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Atorvastatin: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population pharmacokinetics model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender

Atorvastatin: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C_max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.

Renal Impairment

Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial amlodipine dose.

Atorvastatin: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients with renal dysfunction is not necessary [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

Hemodialysis

While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to clear atorvastatin or amlodipine since both drugs are extensively bound to plasma proteins.

Hepatic Impairment

Amlodipine: Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%.

Atorvastatin: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C_max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C_max and AUC of atorvastatin are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4)].

Atorvastatin is contraindicated in patients with active liver disease.

Heart Failure

Amlodipine: In patients with moderate to severe heart failure, the increase in AUC for amlodipine was similar to that seen in the elderly and in patients with hepatic insufficiency.

Effects of Other Drugs on Amlodipine besylate and atorvastatin calcium

Amlodipine:

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors: 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 (7.1)].

Atorvastatin:

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Table 6 shows effects of other drugs on the pharmacokinetics of atorvastatin

Table 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

Co-administered drug and dosing regimen	Atorvastatin
	Dose (mg)	Ratio of AUC&	Ratio of Cmax &
# Cyclosporine 5.2 mg/kg/day, stable dose	10 mg QDa for 28 days	8.69	10.66
# Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days	10 mg, SDc	9.36	8.58
# Glecaprevir 400 mg QDa /pibrentasvir 120 mg QDa , 7 days	10 mg QDa for 7 days	8.28	22.00
# Telaprevir 750 mg q8hf , 10 days	20 mg, SDc	7.88	10.60
#, ‡ Saquinavir 400 mg BIDb /ritonavir 400mg BID, 15 days	40 mg QDa for 4 days	3.93	4.31
# Elbasvir 50 mg QDa /grazoprevir 200 mg QDa , 13 days	10 mg SDc	1.95	4.34
# Simeprevir 150 mg QDa , 10 days	40 mg SDc	2.12	1.70
# Clarithromycin 500 mg BIDb , 9 days	80 mg QDa for 8 days	4.54	5.38
# Darunavir 300 mg BIDb /ritonavir 100 mg BID, 9 days	10 mg QDa for 4 days	3.45	2.25
# Itraconazole 200 mg QDa , 4 days	40 mg SDc	3.32	1.20
# Letermovir 480 mg QDa , 10 days	20 mg SDc	3.29	2.17
# Fosamprenavir 700 mg BIDb /ritonavir 100 mg BIDb , 14 days	10 mg QDa for 4 days	2.53	2.84
# Fosamprenavir 1400 mg BIDb , 14 days	10 mg QDa for 4 days	2.30	4.04
# Nelfinavir 1250 mg BIDb , 14 days	10 mg QDa for 28 days	1.74	2.22
# Grapefruit Juice, 240 mL QDa,*	40 mg, SDc	1.37	1.16
Diltiazem 240 mg QDa , 28 days	40 mg, SDc	1.51	1.00
Erythromycin 500 mg QIDe , 7 days	10 mg, SDc	1.33	1.38
Amlodipine 10 mg, single dose	80 mg, SDc	1.18	0.91
Cimetidine 300 mg QIDe , 2 weeks	10 mg QDa for 2 weeks	1.00	0.89
Colestipol 10 g BIDb , 24 weeks	40 mg QDa for 8 weeks	NA	0.74**
Maalox TC® 30 mL QDa , 17 days	10 mg QDa for 15 days	0.66	0.67
Efavirenz 600 mg QDa , 14 days	10 mg for 3 days	0.59	1.01
# Rifampin 600 mg QDa , 7 days (coadministered) †	40 mg SDc	1.12	2.90
# Rifampin 600 mg QDa , 5 days (doses separated) †	40 mg SDc	0.20	0.60
# Gemfibrozil 600 mg BIDb , 7 days	40 mg SDc	1.35	1.00
# Fenofibrate 160 mg QDa , 7 days	40 mg SDc	1.03	1.02
Boceprevir 800 mg TIDd , 7 days	40 mg SDc	2.32	2.66

^& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

^# See Sections 5.1 and 7 for clinical significance.

* Greater increases in AUC (ratio of AUC up to 2.5) and/or C_max (ratio of C_max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

** Ratio based on a single sample taken 8 to 16 h post dose.

† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.

^a Once daily

^b Twice daily

^c Single dose

^d Three times daily

^e Four times daily

^f Every 8 hours

Effects of Amlodipine besylate and atorvastatin calcium on Other Drugs

Amlodipine:

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Cyclosporine: 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 (7.2)].

Tacrolimus: 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 (7.2)].

Atorvastatin:

Table 7 shows the effects of atorvastatin on the pharmacokinetics of other drugs.

Table 7. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs

Atorvastatin	Co-administered drug and dosing regimen
	Drug/Dose (mg)	Ratio of AUC	Ratio of Cmax
80 mg QDa for 15 days	Antipyrine, 600 mg SDc	1.03	0.89
80 mg QDa for 10 days	# Digoxin 0.25 mg QDa , 20 days	1.15	1.20
40 mg QDa for 22 days	Oral contraceptive QDa , 2 months – norethindrone 1 mg – ethinyl estradiol 35 mcg	1.281.19	1.231.30
10 mg, SD c	Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days	1.08	0.96
10 mg QDa for 4 days	Fosamprenavir 1400 mg BIDb , 14 days	0.73	0.82
10 mg QDa for 4 days	Fosamprenavir 700 mg BIDb /ritonavir 100 mg BIDb , 14 days	0.99	0.94

# See Section 7 for clinical significance.

^a Once daily

^b Twice daily

^c Single dose

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.