Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy

Purpose

Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy.

Methods

This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20–150 mg once daily) or sublingual buprenorphine/naloxone (8/2–24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2–7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7.

Results

Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC _τ ) and maximum observed plasma (or serum) concentration (C _max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC _τ and C _max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess.

Conclusions

There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.

     

Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects

Purpose

Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates.

Methods

Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9.

Results

Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4–5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0–1.4], 1.4-fold (90 % CI 1.2–1.6), and 1.3-fold (90 % CI 1.2–1.4) in the maximum plasma concentration (C_max), area under the concentration–time curve from time 0 to infinity (AUC_0-∞), and terminal half-life (t_1/2), respectively, of midazolam; the time to peak plasma concentration (t_max) was unchanged. Whereas C_max and t_max were not influenced by almorexant, the AUC_0-∞ of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1–1.4) and the t_1/2 by 1.3-fold (90 % CI 1.0–1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0–3.7) and 3.4-fold (90 % CI 2.6–4.4) in C_max and AUC_0-∞, respectively, for simvastatin; the t_1/2 and t_max were unchanged. The C_max and AUC_0-∞ of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3–3.5 and 2.2–3.5, respectively; the t_max increased by 2 h and the t_1/2 was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant.

Conclusions

Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level.     

Effects of ponesimod,a selective S1P1 receptor modulator,on the pharmacokinetics of a hormonal combination contraceptive

Purpose

To determine the effects of steady-state concentrations of the selective S1P₁ receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive.

Methods

Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis.

Results

Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of C_max and AUC_0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of C_max and AUC_0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD?±?6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD?±?5.7) and 1.4 (SD?±?6.4), respectively, at 2.5 h post-dose compared to baseline.

Conclusion

No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.     

Almorexant effects on CYP3A4 activity studied by its simultaneous and time-separated administration with simvastatin and atorvastatin

Purpose

To characterise further the previously observed cytochrome P450 3A4 (CYP3A4) interaction of the dual orexin receptor antagonist almorexant.

Methods

Pharmacokinetic interactions were investigated (n?=?14 healthy male subjects in two treatment groups) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin (40 mg) or atorvastatin (40 mg).

Results

Almorexant dose-dependently increased simvastatin exposure (AUC_0–∞) when administered concomitantly [geometric mean ratios (90 % CI): 2.5 (2.1, 2.9) (100 mg), 3.9 (3.3, 4.6) (200 mg)], but not C_max [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC_0–∞: 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); C_max: 1.5 (1.3, 1.9) (100 mg), 1.9 (1.6, 2.4) (200 mg)]. Similar results were obtained for hydroxyacid simvastatin. Independent of almorexant dose and relative time of administration, AUC_0–∞ and C_max of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC_0–∞ and C_max of o-hydroxy atorvastatin decreased dose-independently [AUC_0–∞: 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); C_max: 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. C_max of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC_0–∞ was unchanged.

Conclusions

Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently, atorvastatin exposure increased to a smaller extent and irrespective of dose and time. This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition.     

Pharmacokinetics,Tolerability, and Safety of the Single Oral Administration of AGSAV301 vs Exforge: A Randomized Crossover Study of Healthy Male Volunteers

Background and Objective

Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S-amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects.

Methods

This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated.

Results

A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C _max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983–1.014), and area under the concentration–time curve from time 0 to last measured time point (AUC_last) was 0.917 (90 % CI 0.861–0.976). The GMR of valsartan C _max was 0.994 (90 % CI 0.918–1.076), and the AUC_last was 0.927 (90 % CI 0.821–1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects.

Conclusions

The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications.     

A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail

Purpose

The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C.

Methods

A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated.

Results

Danoprevir/r and placebo/r significantly increased midazolam area under the time–concentration curve (AUC_0–∞) and reduced the midazolam metabolic ratio while S-warfarin AUC_0–∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC_0–∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC_0–∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar.

Conclusions

Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.     

Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies

Purpose

The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.

Methods

The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C_max, but not for t_max (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C_max and AUC bioequivalence.

Results

The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C_max non-chiral: 82.77–96.09, sum of enantiomers: 82.19–98.23; 90% CI AUC_t non-chiral: 107.23–115.49, sum of enantiomers: 105.73–121.35). However, the chiral method showed differences in AUC and C_max that resulted in non-bioequivalence for the individual enantiomers (90% CI C_max S-ibuprofen: 76.05–91.36, R-ibuprofen: 87.84–113.05; 90% CI AUC_t S-ibuprofen: 96.67–105.86, R-ibuprofen: 118.86–142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.

Conclusions

Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption.     

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.     

Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects

Background

Activated charcoal is commonly used to manage overdose or accidental ingestion of medicines. This study evaluated the effect of activated charcoal on apixaban exposure in human subjects.

Methods

This was an open-label, three-treatment, three-period, randomized, crossover study of single-dose apixaban (20 mg) administered alone and with activated charcoal given at 2 or 6 h post-dose to healthy subjects. Blood samples for assay of plasma apixaban concentration were collected up to 72 h post-dose. Pharmacokinetic parameters, including peak plasma concentration (C _max), time to C _max (T _max), area under the concentration–time curve from time 0 to infinity (AUC_INF), and terminal half-life (T _½), were derived from apixaban plasma concentration–time data. A general linear mixed-effect model analysis of C _max and AUC_INF was performed to estimate the effect of activated charcoal on apixaban exposure.

Results

A total of 18 subjects were treated and completed the study. AUC_INF for apixaban without activated charcoal decreased by 50 and 28 %, respectively, when charcoal was administered at 2 and 6 h post-dose. Apixaban C _max and T _max were similar across treatments. The mean T _½ for apixaban alone (13.4 h) decreased to ~5 h when activated charcoal was administered at 2 or 6 h post-dose. Overall, apixaban was well tolerated in this healthy population, and most adverse events were consistent with the known profile of activated charcoal.

Conclusion

Administration of activated charcoal up to 6 h after apixaban reduced apixaban exposure and facilitated the elimination of apixaban. These results suggest that activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.     

Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy

Purpose

Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC_0-24 and peak concentrations (C _max).

Methods

We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method).

Results

For tobramycin and gentamicin, AUC_0-24 and C _max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC_0-24 could reliably be estimated by both methods. C _max was underestimated by 10–20 % by the two-point method and by up to 30 % with a large variation by the Bayesian method.

Conclusions

The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8–10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.     

Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir

Purpose

Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.

Methods

The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90 % confidence intervals were generated.

Results

The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75 % in DTG AUC_(0–τ), C _max and C _τ , respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76 % in DTG AUC_(0–τ), C _max and C _τ , respectively.

Conclusions

Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.     

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.     

Effect of glycyrrhizin on the activity of CYP3A enzyme in humans

Background

Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin has been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans.

Objective

To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans.

Methods

Sixteen healthy adult male subjects were enrolled in a two-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered and blood samples were obtained to determine midazolam plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMRs) and 90% confidence intervals (90% CI).

Results

The geometric mean (geometric coefficient of variation) for the $ {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} $ of midazolam in the placebo group was 196.4 ng·h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng·h/ml (34.7%). The GMRs and 90% CI for $ {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} $ and C_max of midazolam in the presence/absence of glycyrrhizin were 0.77 (0.70, 0.89) and 0.83 (0.74, 1.01), respectively. The 90% CI for $ {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} $ and C_max for the GMR of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80–1.25.

Conclusions

Administration of glycyrrhizin resulted in a modest induction of CYP3A that was clinically relevant according to the bioequivalence analysis.     

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

Purpose

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.

Methods

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.

Results

A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC)_(0-48h) and C_max 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 t_1/2 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.

Conclusions

Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects.     

High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension

Purpose

To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH).

Methods

Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis.

Results

The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t_max) of 1 h and a mean elimination half-life (t_1/2) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C_max) was 21.4?±?1.7 μg/L, (2) the normalized C_max (C_{max, norm}) 79.1?±?1.6 g/L, (3) the area under the time–concentration curve (AUC) 71.5?±?1.6 μg · h/L and (4) the normalized AUC (AUC_norm) 261.6?±?1.7 g · h/L. Patients co-medicated with bosentan reached t_max later and had a 90% reduction of C_max, C_{max, norm}, AUC and AUC_norm.

Conclusion

The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.     

Pharmacokinetic–Pharmacodynamic Relationships of Macitentan,a New Endothelin Receptor Antagonist,After Multiple Dosing in Healthy Korean Subjects

Background and objectives

Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects.

Methods

A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study.

Results

The concentration–time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t _max] 9–10 h) and slow elimination (mean elimination half-life [t _½] 11–15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C _max) increased as the dose increased and the area under the plasma concentration–time curve during the dosing interval (AUC _τ ) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46–48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events.

Conclusion

Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.     

Tolerability and Pharmacokinetics of Ranolazine Following Single and Multiple Sustained-release Doses in Chinese Healthy Adult Volunteers

Background and Objectives

Ranolazine was approved by the US Food and Drug Administration in January 2006 for the treatment of chronic angina pectoris, and is the first approved agent from a new class of anti-anginal drugs in almost 25 years. The primary objective of this study was to determine the concentration of ranolazine in human plasma using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetic properties of ranolazine after administration of single and multiple doses of ranolazine in healthy Chinese adult volunteers.

Methods

A randomized, open-label, single- and multiple-dose study design was used in the study. Subjects were randomized to receive a single dose of 500, 1,000, or 1,500 mg of ranolazine. Those who received the single dose continued on to the multiple-dose phase and received 500 mg twice daily for 7 days. In the single-dose phase, blood samples were collected from 0 to 48 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am and 8:00 pm on days 6 and 7 to determine the minimum steady-state plasma concentration (C_min,ss) of ranolazine; on day 8, samples were collected from 0 to 48 h after drug administration. All values were expressed as means (standard deviations [SDs]). Adverse events (AEs) were monitored throughout the study via subject interview, vital signs, and blood sampling.

Results

The LC-MS/MS method was developed and validated. Twelve Chinese subjects (six men, six women) were enrolled in the single-dose phase of the pharmacokinetic study. The mean (SD) age of the subjects was 24.7 (1.6) years; their mean (SD) weight was 61.3 (6.4) kg, their mean (SD) height was 165.7 (4.5) cm, and their mean (SD) body mass index was 21.6 (6.6) kg/m². The main pharmacokinetic parameters [mean (SD)] for ranolazine after administration of a single oral dose of 500, 1,000, and 1,500 mg were as follows: maximum plasma concentration (C_max) 741.5 (253.0), 1,355.0 (502.0), and 2,328.7 (890.5) ng/mL, respectively; area under the concentration–time curve from time zero to 48 h (AUC₄₈) 9,071.9 (3,400.0), 16,573.5 (6,806.2), and 29,324.5 (10,857.2) ng·h/mL; AUC from time zero extrapolated to infinity (AUC_∞) 9,826.7 (3,152.0), 16,882.4 (6,790.8), and 29,923.5 (10,706.3) ng·h/mL; time to reach C_max (t_max) 5.3 (1.4), 4.2 (1.2), and 5.9 (2.8) h; elimination half-life (t_½) 6.4 (3.3), 6.4 (3.5), and 6.7 (4.3) h. Mean (SD) values for the main pharmacokinetic parameters for ranolazine after administration of multiple doses were as follows: steady-state C_max (C_max,ss) 1,732.9 (547.3) ng/mL; C_min,ss 838.1 (429.8) ng/mL; steady-state AUC at time t (AUC_ss,(t)) 14,655.5 (5,624.2) ng·h/mL; average steady-state plasma drug concentration during multiple-dose administration (C_av,ss) 1,221.3 (468.7) ng/mL; t_max 3.46 (1.48) h; t_½ 6.28 (2.48) h.

Conclusion

In this group of healthy Chinese subjects, AUC and C_max increased proportionally with the dose, whereas t_½ was independent of the dose. The pharmacokinetic properties of ranolazine were linear after administration of single oral doses of 500 to 1,500 mg. Compared with the pharmacokinetic parameters of the subjects who received a single dose, those who received multiple doses (twice daily) of ranolazine had a larger AUC from time zero to the time of the last measurable concentration (AUC_last), AUC_∞, C_max, and apparent total body clearance of drug from plasma after oral administration (CL/F), and shorter t_max (all p < 0.05). Furthermore, some of the main pharmacokinetic parameters of ranolazine may reflect ethnic differences. This dosage was generally well tolerated by all the subjects.     

Effects of boceprevir and telaprevir on the pharmacokinetics of dolutegravir

AimsThe aim was to evaluate the effect of boceprevir and telaprevir on dolutegravir pharmacokinetics (PK); the effect of dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug''s prescribing information alone.MethodsThis was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2.ResultsNo deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of dolutegravir with boceprevir had no effect on dolutegravir area under the plasma concentration–time curve (AUC) and maximal plasma concentration (C_max) and caused a small increase in concentration at the end of the dosing interval (C_τ; 8%). Coadministration of dolutegravir with telaprevir resulted in increased dolutegravir plasma exposures compared with those after administration of dolutegravir alone; AUC_0–τ, C_max and C_τ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with dolutegravir had no clinically significant effect on dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of dolutegravir on boceprevir or telaprevir exposure.ConclusionsDolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment.     

Does a Hot Drink Provide Faster Absorption of Paracetamol Than a Tablet? A Pharmacoscintigraphic Study in Healthy Male Volunteers

Purpose

To investigate the hypothesis that paracetamol is absorbed faster from a hot drink than from a standard tablet using simultaneous scintigraphic imaging and pharmacokinetic sampling.

Methods

Twenty-five healthy male volunteers received both paracetamol formulations in a randomised manner. The formulation administered in the first treatment arm was radiolabelled to allow scintigraphic monitoring. In both treatment arms, blood samples were taken for assessing paracetamol absorption.

Results

Following the hot drink, paracetamol absorption was both significantly faster and greater over the first 60 min post-dose compared with the tablet, as evidenced by the median time to reach t_0.25?μg/mL of 4.6 and 23.1 min, respectively, and AUC_0-60 of 4668.00 and 1331.17 h*ng/mL, respectively. In addition, t_max was significantly shorter for the hot drink (median time = 1.50 h) compared with the tablet (1.99 h). However, C_max was significantly greater following the tablet (9,077 ng/mL) compared with the hot drink (8,062 ng/mL). Onset of gastric emptying after the hot drink was significantly faster than after the standard tablet (7.9 versus 54.2 min), as confirmed scintigraphically.

Conclusions

Compared with a standard tablet, a hot drink provides faster absorption of paracetamol potentially due to more rapid gastric emptying.     

In Vivo Absorption and Disposition of Cefadroxil After Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

Purpose

To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug.

Methods

The absorption and disposition kinetics of [³H]cefadroxil were determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [³H]cefadroxil were also determined in both genotypes after 44.5 nmol/g intravenous bolus doses.

Results

PepT1 deletion reduced the area under the plasma concentration-time profile (AUC_0-120) of cefadroxil by 10-fold, the maximum plasma concentration (C_max) by 17.5-fold, and increased the time to reach a maximum plasma concentration (T_max) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC_0-120 and C_max values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil were not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations.

Conclusions

The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs.