Pravastatin Sodium: Package Insert and Label Information (Page 4 of 7)

12.3 Pharmacokinetics

General

Absorption: Pravastatin sodium is administered orally in the active form. In studies in man, 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 systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.

Pravastatin plasma concentrations, including area under the concentration-time curve (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.

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.

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).

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 Warnings and Precautions (5.2)].

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 [see Use 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 children (8 to 11 years, N = 14) and adolescents (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 children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [ see Use in Specific Populations ( 8.4) ].

Drug-Drug Interactions

Table 3: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin

Coadministered Drug and Dosing Regimen

Pravastatin

Dose (mg)

Change in AUC

Change in C max

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

20 mg single dose

Administered simultaneously

↓40%

↓39%

Administered 1 hour prior to
cholestyramine

↑12%

↑30%

Administered 4 hours after
cholestyramine

↓12%

↓6.8%

Cholestyramine 24 g OD for 4 weeks

20 mg BID for 8 weeks

↓51%

↑4.9%

5 mg BID for 8 weeks

↓38%

↑23%

10 mg BID for 8 weeks

↓18%

↓33%

Fluconazole

200 mg IV for 6 days

20 mg PO + 10 mg IV

↓34%

↓33%

200 mg PO for 6 days

20 mg PO + 10 mg IV

↓16%

↓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

↓7.0%

↓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%

BID = twice daily; OD = once daily; QID = four times daily

Table 4: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs

Pravastatin Dosing Regimen

Name and Dose

Change in AUC

Change in C max

20 mg BID for 6 days

Warfarin 5 mg OD for 6 days

↑17%

↑15%

Change in mean prothrombin time

↑0.4 sec

20 mg OD for 9 days

Digoxin 0.2 mg OD for 9 days

↑4.6%

↑5.3%

20 mg BID for 4 weeks

Antipyrine 1.2 g single dose

↑3.0%

Not Reported

10 mg BID for 4 weeks

↑1.6%

5 mg BID for 4 weeks

↑ Less than 1%

20 mg OD for 4 days

Kaletra 400 mg/100 mg BID for 14 days

No change

No change

BID = twice daily; OD = once daily

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/m 2) 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.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.

A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52 day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately ≥ 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (≥ 250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.

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