Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients

Aims

Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients.

Methods

Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose).

Results

We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5–175.4) vs. 71.3 (45.6–109.0), P < 0.0001 and 151.8 (112.1–205.6) vs. 109.6 (58.1–132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4–218.0) vs. 119.4 (100.2–166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors.

Conclusions

CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.     

ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients

Purpose

There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients

Methods

The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation.

Results

Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5?±?14.7 vs. 55.1?±?3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR)?4.2, 95 % confidence interval (CI) 1.3–13.9, p?=?0.02 and OR?3.6, 95 % CI 1.1–11.8, p?=?0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR?3.29, 95 % CI 1.1–10.3, p?=?0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes.

Conclusions

ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug’s trough blood concentrations.     

No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin

AIMS

This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics.

METHODS

In a fixed-order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C-c.2677G/G-c.3435C/C (CGC/CGC) genotype and 10 with the c.1236T/T-c.2677T/T-c.3435T/T (TTT/TTT) genotype ingested a single 20-mg dose of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Plasma fluvastatin, pravastatin, and lovastatin concentrations were measured up to 12 h and plasma and urine rosuvastatin concentrations up to 48 and 24 h, respectively.

RESULTS

The ABCB1 genotype had no significant effect on the pharmacokinetics of any of the investigated statins. The geometric mean ratio (95% confidence interval) of the area under the plasma concentration–time curve from 0 h to infinity (AUC_0–∞) in participants with the TTT/TTT genotype to that in those with the CGC/CGC genotype was 0.96 (0.77, 1.20; P= 0.737) for fluvastatin, 0.92 (0.53, 1.62; P= 0.772) for pravastatin, 0.83 (0.36, 1.90; P= 0.644) for lovastatin, 1.25 (0.72, 2.17; P= 0.400) for lovastatin acid, and 1.10 (0.73, 1.65; P= 0.626) for rosuvastatin. The AUC_0–∞ of lovastatin acid correlated significantly with that of rosuvastatin (r= 0.570, P= 0.009), but none of the other AUC_0–∞ pairs showed a significant correlation.

CONCLUSIONS

These data suggest that the ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes play no significant role in the interindividual variability in the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.     

Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers

Purpose

Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies.

Methods

Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n?=?24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n?=?24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥7 days).

Results

Ticagrelor increased mean atorvastatin maximum plasma concentration (C_max) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C_max and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C_max and AUC of analysed atorvastatin metabolites by 13–55 % and 32–67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated.

Conclusions

Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C_max in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided.     

VKORC1-dependent pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation

Objective

The pharmacokinetics of phylloquinone (vitamin K1) were evaluated in healthy human adult volunteers (15 male and 15 female) following oral and intravenous administration of a mixed micelles formulation (Konakion® MM 2 mg) in an open label study design. The subjects were allocated to one of three genotype-specific groups (n?=?10 in each group) in terms of VKORC1 promoter polymorphism c.-1639 G?>?A to explore the relationship between genotype and pharmacokinetic parameters.

Methods

Blood samples were collected for up to 24 h after administration. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. Pharmacokinetic evaluation was performed using non-compartmental analysis.

Results

Pharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in the main pharmacokinetic parameters between groups. Upon oral administration, VKORC1 AG carriers showed 41 % higher mean bioavailability (p?=?0.01) compared with homozygous AA individuals. Furthermore, AG subjects exhibited 30 % (p?=?0.042) and 36 % (p?=?0.021) higher mean AUC compared with GG and AA respectively. Terminal half-life was 32 % and 27 % longer for AG carriers in comparison to GG (p?=?0.004) and AA (p?=?0.015) genotypes respectively.

Conclusion

Pharmacokinetic differences indicated significant inter-individual variance of vitamin K fate in the human body. The influence of the VKORC1 promoter polymorphism c.-1639 G?>?A on the pharmacokinetic properties of phylloquinone could be demonstrated in humans. To gain deeper insight in other potential genetic determinants of systemic vitamin K exposure, further correlation of the phenotype–genotype relationship of different players in vitamin K turnover has to be gained.     

The Acoustic Features of Inhalation can be Used to Quantify Aerosol Delivery from a Diskus™ Dry Powder Inhaler

Purpose

Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery.

Methods

A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n?=?92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus? DPIs. Fine particle fraction, FPF, (<5 μm) was measured at 30–90 l/min for 2–6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 μg) Diskus?, volunteers inhaled either at maximal or minimal effort on separate days.

Results

PIFRc was correlated with spirometrically determined values (R ²?=?0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus? (Adjusted R ²?=?0.95) and was proportional to flow rate only for the salbutamol Diskus? (Adjusted R ²?=?0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p?Conclusion Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.     

Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

Purpose

Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders.

Methods

Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n?=?107) and in treatment-naive patients (n?=?35) and interferon-null responders (n?=?24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference).

Results

The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56–0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39–0.53) compared to volunteers. The mean area under the concentration–time curve (AUC_inf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.

Conclusions

The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.     

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers

Purpose

Ticagrelor is a reversibly binding P2Y₁₂ receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability.

Methods

This was a randomized, double-blind, two-period crossover study in healthy volunteers (n?=?20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14).

Results

Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng?·?h/ml to 21.0 ng?·?h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated.

Conclusions

Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.     

Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers

Purpose

To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate.

Methods

This was an open-label trial in healthy male subjects. In part 1 (pilot, n?=?8) and part 3 (n?=?12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran.

Results

Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC_τ,ss were 135% (90% CI 107–169%) and 132% (90% CI 112–156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC_τ,ss ratio test/reference: 91.9%, 90% CI 78.7–107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC_0?24 was 103%; 90% CI 80.3–131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation.

Conclusions

When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.     

Influence of ABCB1 (P-glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers

AIMS

To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers.

METHODS

Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography.

RESULTS

There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min^–1, P = 0.02). At t_max at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min^–1 on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min^–1 on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group.

CONCLUSION

The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.     

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

Objective

To study the impact of the 79A>C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients.

Patients and methods

Patients (n?=?20) received gemcitabine 1,125 mg/m² as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0–6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A>C genotype was determined with PCR and DNA sequencing.

Results

Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A>C polymorphism was 0.40. Diplotypes were distributed as A/A n?=?8, A/C n?=?8 ,and C/C n?=?4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life.

Conclusion

The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.     

Effects of Ginkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects

Aim

It has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that GBE may alter the metabolism of diazepam.

Methods

The pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or presence of oral GBE (120 mg bid, for 28 days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method.

Results

The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80–125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC_0–408 with GBE to AUC_0–408 without GBE was 95.2 (90%CI: 91.6–98.8) and 101.8 (90%CI: 99.4–104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported.

Conclusion

The above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.     

Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers

Purpose

Nateglinide is commonly used in the treatment of patients with type 2 diabetes mellitus. Our objective was to assess the association between CYP2C9 and SLCO1B1 polymorphisms and the metabolism of nateglinide in healthy Chinese male volunteers.

Methods

A total of 35 healthy Chinese male volunteers with different CYP2C9 and SLCO1B1 genotypes were given a single oral dose of 120 mg nateglinide. Plasma concentrations of nateglinide and blood glucose level were measured up to 8 h.

Results

In subjects with the CYP2C9*1/*3 & 521TT, CYP2C9*1/*1 & 521TC/CC and CYP2C9*1/*3 & 521TC genotype, AUC_0-∞ of nateglinide was 56 %, 34 % and 56 % higher (P?=?0.002, P?=?0.041 and P?=?0.013, respectively), and the CL/F of nateglinide was 35 %, 11 % and 36 % lower (P?=?0.000, P?=?0.003 and P?=?0.002, respectively) than that in the reference group. When only considering 521 T>C polymorphism, it had no significant association with the pharmacokinetics of nateglinide. CYP2C9*3 and 521 T>C polymorphisms were the significant predictors of the AUC_0-∞ and CL/F of nateglinide (adjusted multiple R ² ?=?34 % and 43 %, respectively) according to multiple linear regression analyses, but they have no significant association with changes in the blood glucose-lowering effect of nateglinide.

Conclusions

Both SLCO1B1 521 T>C and the CYP2C9*3 polymorphisms can significantly affect the pharmacokinetics of nateglinide, but they could only partially explain the interindividual variability of plasma concentration of nateglinide. Moreover, 521 T>C and the CYP2C9*3 polymorphisms have no effect on pharmacodynamics of nateglinide in healthy Chinese male subjects.     

Coadministration of Dabigatran Etexilate and Atorvastatin

Background

Dabigatran etexilate, a novel oral direct thrombin inhibitor, has been approved for prophylaxis of thromboembolism in patients undergoing total knee or total hip replacement, and is under clinical investigation for treatment of venous thromboembolism, prevention of stroke in patients with atrial fibrillation, and the treatment of thromboembolic complications following acute coronary syndromes.

Objective

To evaluate the potential impact of atorvastatin coadministration on the pharmacokinetics, pharmacodynamics, and safety of dabigatran etexilate.

Methods

Healthy male and female volunteers (n = 22) were recruited to this open, randomized, multiple-dose, three-way crossover study. They received dabigatran etexilate 150 mg twice daily on days 1–3 and once daily on day 4, atorvastatin 80 mg once daily on days 1–4, or both treatments together on days 1–4.

Results

Exposure to dabigatran at steady state (area under the drug plasma concentration-time curve at steady state) was reduced by 18% with concomitant atorvastatin administration. An 18% increase in plasma atorvastatin concentration occurred with coadministration of dabigatran etexilate. Exposure to its metabolite 2′-hydroxy-atorvastatin remained essentially unchanged and exposure to 4′-hydroxy-atorvastatin was increased by 15%. The small changes observed are deemed of little clinical relevance given the overall interindividual variability in the metabolism of atorvastatin. Furthermore, there were no changes in the concentrations of active HMG-CoA reductase inhibitors in plasma following dabigatran etexilate coadministration. Six subjects in the atorvastatin treatment group, six subjects during combination treatment, and eight subjects in the dabigatran treatment group reported adverse events. Most of the adverse events reported were nervous system disorders such as dizziness and headache, and general disorders such as fatigue. All adverse events were resolved at the end of the study.

Conclusion

Results of this randomized, open-label, three-way crossover design study in healthy male and female volunteers showed that atorvastatin had no influence on the pharmacokinetic/pharmacodynamic profile of dabigatran, and vice versa, dabigatran etexilate had no impact on the pharmacokinetic/pharmacodynamic profile of atorvastatin. Both drugs were well tolerated when given alone or in combination.     

Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers

Purpose

To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration–time profiles among OATP1B substrates drugs and endogenous substrates.

Methods

Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined.

Results

The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC_0–24h of atorvastatin was reasonably correlated with that of pitavastatin (r²?=?0.73) and with the AUC_0–4h of fluvastatin (r²?=?0.62) and sufficiently with the AUC_0–24h of rosuvastatin (r²?=?0.32). The AUC_0–24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r²?=?0.74) and coproporphyrin I (r²?=?0.80), and sufficiently with that of total bilirubin (r²?=?0.30). The AUC_0–24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r²?=?0.54–0.70).

Conclusion

These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.

     

The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects

Purpose

Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated.

Methods

This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n?=?20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period.

Results

Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration–time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P?<?0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P?<?0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration–time curve of metformin.

Conclusions

Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.     

The population pharmacokinetics of allopurinol and oxypurinol in patients with gout

Purpose

The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics.

Methods

Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent–metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling.

Results

Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively.

Conclusions

The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.     

Lack of effect of continuous glycyrrhizin administration on the pharmacokinetics of the P-glycoprotein substrate talinolol in healthy volunteers

Purpose

To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans.

Methods

Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration–time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05.

Results

All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC_0–∞ for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3?±?724.3 and 1,988.2?±?649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC_0–∞ and C _max fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC_0–∞, AUC_0–24, C _max, t _max, t _½) for talinolol.

Conclusions

Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate.