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.     

Lack of impact of artesunate on the disposition kinetics of sulfadoxine/pyrimethamine when the two drugs are concomitantly administered

Objective

To determine the effect of artesunate (AT) on the disposition kinetics of sulfadoxine/pyrimethamine (SP) in humans.

Methods

In a randomized cross-over study, 16 healthy volunteers were given a dose of three SP tablets containing 500 mg of sulfadoxine (SDX) and 25 mg of pyrimethamine (PYR) (=SP group), while the second arm received three SP tablets + two AT tablets of 200 mg in total followed by 100 mg AT for the next 4 days (SP+AT group). Blood samples (100 μl) were collected by means of a finger prick and dried on filter paper. The blood spots were wrapped in polythene folders and stored at room temperature until analysis. The samples were assayed using high-performance liquid chromatographic methods.

Results

The peak concentration C_max), time required to attain peak concentration (T_max), half-life (t _½) and area under the plasma concentration-time curve (AUC) were determined. The C_max of SDX were 92.9 and 98.9 μg/ml for the SP and SP+AT arms, respectively; for PYR, these were 0.86 and 0.79 μg/ml, respectively. The T_max of SDX were 10 and 8 h for the SP and SP+AT arms, respectively; for PYR, these were 4.0 and 3.0 h, respectively. The AUC_0–288 of SDX were 15,840 and 18,876 μg/ml h for the SP and SP+AT arms, respectively; for PYR, they were 124 and 112 μg/ml h, respectively. The t _½ of values for SDX were 165 and 180 h for the SP and SP+AT arms, respectively; for PYR, these were 158 and 177 h, respectively. There was no statistically significant difference between the C_max, T_max, AUC_0–288 and t _½ between the two arms (p?>?0.05).

Conclusion

Taking AT concomitantly with SP does not have any impact in the disposition of SP.

     

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.     

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.     

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.     

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.     

Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?

Objective

We have investigated the arterio–venous difference in the pharmacokinetics of 50 μg fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naïve middle-aged to elderly patients.

Methods

Twelve male patients (range in age 47–84 years) scheduled for transurethral resection of the prostate gland received a 100-μl dose of 50 μg fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded.

Results

The arterial C_max (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C_max of 0.47 ng/ml, and the arterial T_max (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T_max of 11.6 min. The arterial AUC_0-60 (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC_0-60 of 15 min*ng/ml (all p values?≤?0.005). Venous T_max and C_max did not predict the corresponding arterial values. No significant adverse events were observed.

Conclusion

A significant arterio–venous difference was present after intranasal administration of fentanyl. The short arterial T_max complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-μg dose of nasal fentanyl was well tolerated by opioid-naïve middle-aged to elderly male patients.

     

Pharmacokinetic and pharmacodynamic interactions between the hepatitis C virus protease inhibitor,boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone

Purpose

The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE).

Methods

A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days.

Results

Coadministration of boceprevir with EE/NE did not affect NE AUC_0–24 but slightly reduced NE C _max. Geometric mean ratios (GMRs) for NE AUC_0–24 and C _max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90 % confidence interval (CI), 0.87–1.06) and 0.83 (90 % CI, 0.76–0.90). Coadministration of boceprevir with EE/NE reduced EE AUC_0–24 and C _max by 26 and 21 %, with GMRs of 0.74 (90 % CI, 0.68–0.80) and 0.79 (90 % CI, 0.75–0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir.

Conclusion

Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established.     

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.     

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.     

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.     

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.     

Pharmacokinetics of teduglutide in subjects with renal impairment

Purpose

Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics.

Methods

This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUC_inf and C_max) were calculated.

Results

Area under the concentration versus time curve extrapolated to infinity (AUC_inf) and maximum plasma concentration (C_max) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUC_inf and C_max were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups.

Conclusions

In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns.     

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.     

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.     

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Objectives

To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC).

Methods

Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson’s disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C_min, C_max, C_max???C_min, AUC, t_1/2, and t_max.

Results

In healthy volunteers and PD patients, mean trough levels (C_min), C_max, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C_min, C_max, and AUC, differences between the treatments in variability of levodopa concentrations (C_max???C_min) were less consistent.

Conclusions

The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson’s disease using similar dosing regimens.     

Edoxaban population pharmacokinetics and exposure–response analysis in patients with non-valvular atrial fibrillation

Purpose

The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure–response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF).

Methods

Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients.

Results

Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V ₂), resulting in a predicted increase of 33–77 % in area under the curve (AUC) and 65–104 % in C _max. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C ₂₄, ?24 to 38 %), due to decreased V ₂ and shortened elimination half-life. With IV dosing of edoxaban, co-administration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V ₂, resulting in an increase of 32 % in AUC and 66 % in C ₂₄. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C _min was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure–response analysis suggested that edoxaban C _min and country/region are significantly associated with the incidence of bleeds.

Conclusions

The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials.     

Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2 h apart

Background

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most abused recreational drugs. Its usual pattern of misuse includes repeated doses taken over a short time period that could influence MDMA pharmacology and toxicity.

Objective

This study aims to evaluate the pharmacokinetics and pharmacologically induced effects of two MDMA consecutive doses separated by 2 h.

Methods

A randomized, double-blind, crossover, and placebo-controlled trial included ten male volunteers participating in two experimental sessions. MDMA was administered as a single 100-mg dose or as a repeated dose (50 mg followed by 100 mg, administered at 2 h apart). Outcome variables included pharmacokinetics, physiological, subjective, and psychomotor effects.

Results

Following the repeated doses, plasma concentrations of MDMA were higher than those expected by simple dose accumulation (+16.2 % AUC; +12.8 % C _max), but those of HMMA and HMA were significantly lower (?29.8 % AUC; ?38.2 % C _max). After the second dose, physiological effects, psychomotor performance, and subjective effects were lower than expected especially for euphoria and stimulation. MDMA-induced increases in diastolic and systolic arterial pressure and body temperature were in the range of those expected following MDMA concentrations.

Conclusions

MDMA pharmacokinetics and metabolic disposition following two doses separated by 2 h show that the contribution of the first dose to the MDMA-induced mechanism-based metabolic inhibition was already apparent. The concentrations of MDMA after the second dose were slightly higher than expected. The effects on blood pressure and temperature after the second administration were slightly higher than those following the first, but for heart rate and subjective variables these were lower than expected considering the MDMA concentrations achieved, suggesting a possible tolerance phenomenon.