Pharmacokinetics Of Pitavastatin Research Articles

Pharmacokinetic herb-disease-drug interactions: Effect of ginkgo biloba extract on the pharmacokinetics of pitavastatin, a substrate of Oatp1b2, in rats with non-alcoholic fatty liver disease

Ethnopharmacological relevanceGinkgo biloba L. is a traditional Chinese medicine for hyper lipaemia. Ginkgo flavonols and terpene lactones are responsible for the lipid-lowering effect in non-alcoholic fatty liver disease (NAFLD). However, the pharmacokinetics of ginkgo flavonols and terpene lactones in NAFLD was not clarified. Aim of the studyTo investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats. Materials and methodsMale rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of 3H-ES were tested in hOATP1B1-HEK293 cells. ResultsThe plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6–32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2–3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the Cmax and AUC0-t of pitavastatin by 1.8–3.2 and 1.3–3.0 folds, respectively. In hOATP1B1-HEK293 cells, kaempferol and isorhamnetin contributed to the inhibition of OATP1B1-mediated uptake of 3H-ES with IC50 values of 3.28 ± 1.08 μM and 46.12 ± 5.25 μM, respectively. ConclusionsNAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.

Effects of capsaicin on pharmacokinetics of pitavastatin in rats

1. Capsaicin (CAP) is the primary pungent principle in peppers and an inhibitor of CYP3A subfamily and P-gp.2. Pitavastatin is mainly metabolized via glucuronidation and metabolism by hepatic CYPs is minimal. Pitavastatin is taken up by Oatp1b2 (encoded by Slco1b2) in rat.3. The pharmacokinetics results showed that AUC and Cmax in the group pre-treated with 3 mg/kg/d CAP were increased by 1.2 fold and 1.6 fold; AUC and Cmax in the group pre-treated with 8 mg/kg/d CAP were increased by 2.1 fold (p < 0.05) and 2.9 fold (p < 0.05); AUC and Cmax in the group pre-treated with 25 mg/kg/d CAP were increased by 2.0 fold and 1.9 fold. The RT-PCR data indicated that pretreatment with CAP had little influence on the mRNA expression level of Slco1b2 in liver. These results demonstrated that chronic ingestion of CAP increases the bioavailability of pitavastatin in rat and that Oatp1b2 gene expression in rat liver is hardly effected by CAP.

Effect of a single-dose rifampin on the pharmacokinetics of pitavastatin in healthy volunteers

As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers. Twelve Chinese healthy male volunteers took 4 mg pitavastatin orally with 150 ml water or with a single dose of 600 mg rifampin on separate occasions and the plasma concentrations of pitavastatin were measured over 48 h by HPLC-MS/MS. A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC)(0-48 h) and Cmax of pitavastatin by 573.5 %(95%CI, 373.3-773.7 %, p < 0.001) and 819.2 %(95 % CI, 515.4-1123.0 %, p < 0.001) respectively, while significantly decreased the t1/2 and CL/F of pitavastatin by 38.8 % (95 % CI, 18.2-59.4 %, p < 0.001) and 81.4 % (95 % CI, 75.0-87.7 %, p < 0.001) respectively. Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects.

Impact of ABCC2, ABCG2 and SLCO1B1 Polymorphisms on the Pharmacokinetics of Pitavastatin in Humans

Pitavastatin, a 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitor is distributed to the liver, a target organ of action and excreted mainly into the bile. To investigate the impact of influx (OATP1B1) and efflux (MRP2, BCRP) transporter alleles on its disposition, the pharmacokinetic (PK) parameters were compared among the following groups: SLCO1B1 (*15 carrier and non-carrier), ABCC2 (G1249A, C3972T, C-24T, G1549A, and G1774T), and ABCG2 (C421A) single nucleotide polymorphisms in 45 healthy Korean volunteers. Pitavastatin AUC(last) was higher in individuals carrying the SLCO1B1*15 allele than those not carrying it (144.1 ± 55.3 vs. 84.7 ± 25.7 h·ng/mL [mean ± SD], p = 0.002). The AUC(last) varied significantly according to the ABCC2 C-24T allele (103.4 ± 42.2, 80.2 ± 23.8, and 39.0 h·ng/mL in CC, CT and TT, respectively; p = 0.027). Other SNPs of ABCC2 and ABCG2 were not significant. The effect of these transporters and body weight on the AUC(last) and C(max) were tested, and only SLCO1B1 and ABCC2 C-24T genotypes were significant factors by analysis of covariance. These variants accounted for almost 50% of the variation in AUC(last) and C(max) of pitavastatin. Therefore, ABCC2 C-24T was significantly associated with pitavastatin human PK when the known effect of SLCO1B1*15 was also considered.

Effects of Steady-State Lopinavir/Ritonavir on the Pharmacokinetics of Pitavastatin in Healthy Adult Volunteers

Pitavastatin, a statin recently approved in the United States, has a potential benefit of reduced risk of cytochrome P450 (CYP)-mediated drug-drug interaction due to minimal metabolism by the CYP system. The primary objective was to investigate pharmacokinetic (PK) effects of lopinavir/ritonavir 400 mg/100 mg twice daily on pitavastatin 4 mg when coadministered. This was an open-label one-arm study. Pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24). Lopinavir/ritonavir 400 mg/100 mg was administered twice daily (days 9-24). Plasma samples for PK assessments were collected on days 5, 19, and 24. Plasma concentrations of analytes were determined by liquid chromatography with tandem mass spectrometric detection methods. PK data were available for 23 of 24 subjects enrolled. For pitavastatin, area under the concentration time curve (AUC0-τ) and maximum concentration (C(max)) were 136.8 ± 52.9 ng·h(-1)·mL(-1) and 58.6 ± 30.4 ng/mL, respectively, when given alone, versus 113.9 ± 53.8 ng·h(-1)·mL(-1) and 58.2 ± 32.7 ng/mL when combined with lopinavir/ritonavir. The geometric mean ratio for AUC(0-τ) for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and C(max) was 96.1 (90% confidence interval: 83.6 to 110.4). Median T(max) of pitavastatin was approximately 0.5 hours for both treatments. The PK effect of pitavastatin on lopinavir/ritonavir was minimal. No significant safety issues were reported. The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated in healthy adult volunteers.

Effects of the SLCO1B1*15 allele on the pharmacokinetics of pitavastatin

The hepatic uptake of pitavastatin is mediated by carriers, especially OATP1B1, which is encoded by the SLCO1B1 gene. Because the liver is a target organ of pitavastatin, OATP1B1 is responsible for both the pharmacological effects and clearance of pitavastatin. The effects of the SLCO1B1*15 allele on the pharmacokinetics (PK) of pitavastatin were studied.Pitavastatin 2 mg was orally administered to 38 subjects with SLCO1B1*1a/*1b (n = 20), *1b/*15 (n = 13), or *15/*15 (n = 5). After pitavastatin administration, the plasma concentrations of pitavastatin and pitavastatin lactone were assayed for up to 48 h using liquid chromatography-tandem mass spectrometry.In comparison to the SLCO1B1*1a/*1b subjects, only a Cmax was slightly higher in the SLCO1B1*1b/*15 subjects. However, the SLCO1B1*15/*15 subjects had a 1.74-fold higher AUCinf (285.5 ± 14.5 vs. 164.6 ± 41.3 ng·h/mL; p < 0.001), a 2.21-fold higher Cmax (106.7 ± 15.1 vs. 48.3 ± 13.4 ng/mL; p < 0.001), and a 47.3% lower apparent oral clearance (13.1 ± 3.9 vs. 6.9 ± 0.4 L/h; p < 0.001) of pitavastatin.For pitavastatin lactone, there were no significant differences in AUCinf, Cmax, t1/2, and tmax among the three genotypes.Unlike previous studies, the disposition of pitavastatin exposure was not altered in subjects with the SLCO1B1*1b/*15 genotype, except Cmax. However, pitavastatin exposure was significantly increased in subjects with the SLCO1B1*15/*15 genotype due to reduced hepatic absorption.

Pitavastatin – pharmacological profile from early phase studies

Pitavastatin has been designed as a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with a novel cyclopropyl moiety that results in several differences compared to other statins. These include effective inhibition of cholesterol synthesis and increased lipoprotein lipase expression at lower doses than other statins, and significant high-density lipoprotein-cholesterol and apolipoprotein A1-elevating activity that persists with time. The safety, tolerability and pharmacokinetics of pitavastatin and its major metabolite, pitavastatin lactone, have been investigated in a variety of patient groups with similar results, which suggests dosage adjustments are not required for gender, age or race. In healthy subjects, pitavastatin is well tolerated at the approved doses with no serious adverse events. The bioavailability of pitavastatin is, at 60%, higher than that of any other statin and the majority of the bioavailable fraction of an oral dose is excreted unchanged in the bile. The entero-hepatic circulation of unchanged drug contributes to the prolonged duration of action and allows once-daily, any-time dosing. Pitavastatin is only slightly metabolised by cytochrome P450 (CYP) 2C9 and not at all by CYP3A4. Neither pitavastatin nor its lactone form, have inhibitory effects on CYP, and CYP3A4 inhibitors have no effect on pitavastatin concentrations. Moreover, P-glycoprotein-mediated transport does not play a major role in the drug's disposition and pitavastatin does not inhibit P-glycoprotein activity. Pitavastatin is transported into the liver by several hepatic transporters but OATP1B1 inhibitors have relatively little effect on plasma concentrations compared with other statins. In general, interactions, except with multi-transporter inhibitors like ciclosporin, are not clinically significant. Consequently, pitavastatin has minimal drug-food and drug-drug interactions making it a treatment option in the large group of dyslipidaemic people that require multidrug therapy.

OATP1B1 388A&gt;G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild-type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C(max)) value was higher in the 388GA + 388GG group than that in the 388AA group (39.22 +/- 8.45 vs. 22.90 +/- 4.03 ng/mL, P = 0.006). The area under the curve to the last measurable concentration (AUC(0-48)) and area under the curve extrapolated to infinity (AUC(0-infinity)) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100.42 +/- 21.19 vs. 182.19 +/- 86.46 ng h/mL, P = 0.024; 108.12 +/- 24.94 vs. 199.64 +/- 98.70 ng h/mL, P = 0.026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12.46 +/- 4.79 vs. 19.21 +/- 3.74/h, P = 0.012). The elimination of half-life (t(1/2)) and peak concentration times (T(max)) values showed no difference between these groups. The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.

SLCO1B1 (OATP1B1, an Uptake Transporter) and ABCG2 (BCRP, an Efflux Transporter) Variant Alleles and Pharmacokinetics of Pitavastatin in Healthy Volunteers

To investigate the contribution of genetic polymorphisms of SLCO1B1 and ABCG2 to the pharmacokinetics of a dual substrate, pitavastatin, 2 mg of pitavastatin was administered to 38 healthy volunteers and pharmacokinetic parameters were compared among the following groups: 421C/C(*)1b/(*)1b (group 1), 421C/C(*)1b/(*)15 (group 2), 421C/C(*)15/(*)15 and 421C/A(*)15/(*)15 (group 3), 421C/A(*)1b/(*)1b (group 4), 421A/A(*)1b/(*)1b (group 5), and 421C/A(*)1b/(*)15 (group 6). In SLCO1B1, pitavastatin area under plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for groups 1, 2, and 3 was 81.1+/-18.1, 144+/-32, and 250+/-57 ng h/ml, respectively, with significant differences among all three groups. In contrast to SLCO1B1, AUC(0-24) in groups 1, 4, and 5 was 81.1+/-18.1, 96.7+/-35.4, and 78.2+/-8.2 ng h/ml, respectively. Although the SLCO1B1 polymorphism was found to have a significant effect on the pharmacokinetics of pitavastatin, a nonsynonymous ABCG2 variant, 421C>A, did not appear to be associated with the altered pharmacokinetics of pitavastatin.

Effect of () variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone. OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.

Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin

To compare the effects of grapefruit juice (GFJ) on the pharmacokinetics of pitavastatin and atorvastatin. In a randomized, four-phase crossover study, eight healthy subjects consumed either GFJ or water t.i.d. for 4 days in each trial. On each final day, a single dose of 4 mg pitavastatin or 20 mg atorvastatin was administered. GFJ increased the mean AUC(0-24) of atorvastatin acid by 83% (95% CI 23-144%) and that of pitavastatin acid by 13% (-3 to 29%). Pitavastatin, unlike atorvastatin, appears to be scarcely affected by the CYP3A4-mediated metabolism.

An open-label study on the pharmacokinetics (PK) of pitavastatin (NK-104) when administered concomitantly with fenofibrate or gemfibrozil in healthy volunteers

The objective of this study was to compare the steady state (SS) PK of Pitavastatin (NK-104) before and after coadministration with either fenofibrate or gemfibrozil as interactive agents for 7 days. In this single-center, open-label, one-sequence, crossover study, 24 healthy subjects aged 18 to 45 years who met qualifying criteria were enrolled. PK of NK-104 and its lactone at SS were assessed after administration of NK-104 (4mg QD) for Days 1 through 6 and after coadministration with either fenofibrate (160mg QD) or gemfibrozil (600mg BID) on Days 8 through 14. Differences in log transformed PK parameters between the two treatments were estimated using ANOVA and their associated 90% confidence intervals (CI) were inversely transformed to obtain the ratios. No drug-drug interaction was claimed if the 90% CI fell entirely within the range of 80%-125%. Fenofibrate coadministration showed equivalence in the CmaxSS of NK-104, NK-104 lactone and AUC(0–24)SSof NK-104 lactone and increased the NK-104 AUC(0–24)SS by 18%. Gemfibrozil coadministration increased the CmaxSS of NK-104 by 31%, AUC(0–24)SS by 45% and decreased the CmaxSS of NK-104 lactone by 28% and AUC(0–24)SS by 15%. Both fenofibrate and gemfibrozil were observed to lower the amount of NK-104 lactone excreted in urine and NK-104 lactone renal clearance. The coadministration of either fenofibrate or gemfibrozil with NK-104 for 7 days was found to be safe, well tolerated and without clinically significant PK interactions. Clinical Pharmacology & Therapeutics (2004) 75, P33–P33; doi: 10.1016/j.clpt.2003.11.125

Effect of Biliary Excretion on the Pharmacokinetics of Pitavastatin (NK-104) in Dogs.

The disposition of pitavastatin and pitavastatin lactone, which are mutually converted in the circulatory system, was investigated after intravenous administration of pitavastatin in dogs equipped with chronic bile-duct catheters. The plasma concentration of pitavastatin declined three-exponentially after dosing in the dogs with both diverted and non-diverted bile-flow. The terminal elimination half-life (T1/2) of pitavastatin in the diverted and non-diverted conditions was 3.12 and 5.01 hr, and that of pitavastatin lactone 4.50 and 7.23 hr, respectively. The diverted bile-flow decreased the AUC0-24 hr for pitavastatin and its lactone to 66 and 64%, respectively. In the dogs with the diverted bile-flow, 56.1% and 4.2% of the dose was recovered in the bile as pitavastatin and its lactone, respectively. The biliary clearance (CLb) of pitavastatin and its lactone was 32.5 and 6.8 mL/min, respectively, and the CLb of pitavastatin was about 4.8-fold that of its lactone. In the dogs whose bile-flow was not diverted, the cumulative biliary excretion of pitavastatin and its lactone was estimated from the AUC0-24 hr and CLb of both forms of pitavastatin. The estimated amount was increased by 46% compared with that in the dogs with the diverted bile-flow. This indicates that the increase reflects the actual contribution of the enterohepatic circulation.