Pravastatin Sodium: Package Insert and Label Information (Page 3 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics

Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of pravastatin sodium is usually achieved by 4 weeks and is maintained after that.

12.3 Pharmacokinetics

Absorption

Pravastatin sodium is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and Cmax by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.

Pravastatin plasma concentrations, including AUC, C_max , and steady-state minimum (C_min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose.

The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C_max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, C_max , and C_min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets.

Distribution

Approximately 50% of the circulating drug is bound to plasma proteins.

Elimination

Metabolism

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).

Excretion

Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation).

Following single dose oral administration of ¹⁴ C-pravastatin, the radioactive elimination t_½ for pravastatin is 1.8 hours in humans and the elimination half-life (t_½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours.

Specific Populations

Renal Impairment

A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C_max values, respectively, and a 0.61 hour shorter t_½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations (8.6)].

Hepatic Impairment

In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations (8.6)].

Geriatric

In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C_max , T_max , and t_½ values were similar in older and younger subjects [seeUse in Specific Populations (8.5) ].

Pediatric

After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for C_max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [seeUse in Specific Populations (8.4) ].

Drug-Drug Interactions

Table 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin

	Pravastatin
Coadministered Drug and Dosing Regimen	Dose (mg)	Change in AUC	Change in Cmax
BID = twice daily; OD = once daily; QID = four times daily
Cyclosporine 5 mg/kg single dose	40 mg single dose	↑282%	↑327%
Clarithromycin 500 mg BID for 9 days	40 mg OD for 8 days	↑110%	↑128%
Boceprevir 800 mg TID for 6 days	40 mg single dose	↑63%	↑49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days	40 mg single dose	↑81%	↑63%
Colestipol 10 g single dose	20 mg single dose	↓47%	↓53%
Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine	20 mg single dose	↓40%↑12%↓12%	↓39%↑30%↓6.8%
Cholestyramine 24 g OD for 4 weeks	20 mg BID for 8 weeks5 mg BID for 8 weeks10 mg BID for 8 weeks	↓51%↓38%↓18%	↑4.9%↑23%↓33%
Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days	20 mg PO+10 mg IV20 mg PO+10 mg IV	↓34%↓16%	↓33%↓16%
Kaletra 400 mg/100 mg BID for 14 days	20 mg OD for 4 days	↑33%	↑26%
Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days	40 mg single dose	↑31%	↑42%
Cimetidine 300 mg QID for 3 days	20 mg single dose	↑30%	↑9.8%
Antacids 15 mL QID for 3 days	20 mg single dose	↓28%	↓24%
Digoxin 0.2 mg OD for 9 days	20 mg OD for 9 days	↑23%	↑26%
Probucol 500 mg single dose	20 mg single dose	↑14%	↑24%
Warfarin 5 mg OD for 6 days	20 mg BID for 6 days	↓13%	↑6.7%
Itraconazole 200 mg OD for 30 days	40 mg OD for 30 days	↑11% (compared to Day 1)	↑17% (compared to Day 1)
Gemfibrozil 600 mg single dose	20 mg single dose	↓7%	↓20%
Aspirin 324 mg single dose	20 mg single dose	↑4.7%	↑8.9%
Niacin 1 g single dose	20 mg single dose	↓3.6%	↓8.2%
Diltiazem	20 mg single dose	↑2.7%	↑30%
Grapefruit juice	40 mg single dose	↓1.8%	↑3.7%

Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs

Pravastatin Dosing Regimen	Name and Dose	Change in AUC	Change in Cmax
BID = twice daily; OD = once daily
20 mg BID for 6 days	Warfarin 5 mg OD for 6 daysChange in mean prothrombin time	↑17%↑0.4 sec	↑15%
20 mg OD for 9 days	Digoxin 0.2 mg OD for 9 days	↑4.6%	↑5.3%
20 mg BID for 4 weeks10 mg BID for 4 weeks5 mg BID for 4 weeks	Antipyrine 1.2 g single dose	↑3%↑1.6%↑ Less than 1%	Not Reported
20 mg OD for 4 days	Kaletra 400 mg/100 mg BID for 14 days	No change	No change

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m²) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.

No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child.