Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase

AIM

This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.

METHODS

Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed.

RESULTS

Mean febuxostat C_max, AUC_(0–t), AUC_(0–∞), t_1/2,z, CL/F and V_ss/F values for regimens co-administration/febuxostat alone were 2.9/2.9 µg ml⁻¹, 9.3/9.1 µg ml⁻¹ h, 9.6/9.3 µg ml⁻¹ h, 6.5/6.1 h, 8.8/9.3 l h⁻¹ and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C_max, AUC_(0–t), and AUC_(0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C_mean,24h, C_mean,48h and CL_R for both regimens co-administration/febuxostat alone were 216/203 µmol l⁻¹, 218/202 µmol l⁻¹ and 9.1/10.1 ml min⁻¹, respectively. Although serum uric acid C_mean,24h and C_mean,48h values were higher and CL_R values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant.

CONCLUSION

Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.     

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women

AIMS

Oral contraceptives such as norgestimate–ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate–ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)].

METHODS

In each of two periods, nineteen healthy women established on norgestimate–ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1–21. Pharmacokinetics were analysed on day 21 of each period.

RESULTS

The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate–ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93–1.04) for the area under the concentration–time curve from 0 to 24 h (AUC_{0–24 h}) and 1.06 (0.98–1.14) for the maximum concentration of drug in the plasma (C_max); the GMR (90% CI) for the NGMN component of norgestimate–ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08–1.21) for AUC_{0–24 h} and 1.29 (1.23–1.37) for C_max. There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience.

CONCLUSIONS

Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.     

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

AIMS

To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.

METHODS

In this open-label, two-treatment, crossover study, subjects (n = 14) aged 20–41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1–9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C_max (t_max), and half-life (t_1/2) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC_INR), maximum INR (INR_max), area under the PT-time curve (AUC_PT) and maximum PT (PT_max).

RESULTS

Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92–100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.

CONCLUSIONS

The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.     

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

AIMS

Ambrisentan is an oral, propanoic acid-based endothelin receptor antagonist often co-administered with warfarin to patients with pulmonary arterial hypertension. The aim of this study was to evaluate the potential for ambrisentan to affect warfarin pharmacokinetics and pharmacodynamics.

METHODS

In this open-label cross-over study, 22 healthy subjects received a single dose of racemic warfarin 25 mg alone and after 8 days of ambrisentan 10 mg once daily. Assessments included exposure (AUC_0–last) and maximum plasma concentration (C_max) for R-and S-warfarin, and International Normalized Ratio maximum observed value (INR_max) and area under the curve (INR_{AUC(0–last)}). The effects of warfarin on ambrisentan steady-state pharmacokinetics and the safety of ambrisentan/warfarin co-administration were assessed. Data are presented as geometric mean ratios.

RESULTS

Ambrisentan had no significant effects on the AUC_0–last of R-warfarin [104.7; 90% confidence interval (CI) 101.7, 107.7) or S-warfarin (101.6; 90% CI 98.4, 105.0). Similarly, ambrisentan had no significant effects on the C_max of R-warfarin (91.6; 90% CI 86.2, 97.4) or S-warfarin (89.9; 90% CI 84.8, 95.3). Consistent with these observations, little pharmacodynamic change was observed for INR_max (85.3; 90% CI 82.4, 88.2) or INR_{AUC(0–last)} (93.0; 90% CI 90.8, 95.3). In addition, co-administration of warfarin did not alter ambrisentan steady-state pharmacokinetics. Adverse events were infrequent, and there were no bleeding adverse events.

CONCLUSIONS

Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin. Therefore, significant dose adjustments of either drug are unlikely to be required with co-administration.     

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

Aims

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics.

Methods

Healthy subjects, 18–55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1–2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days.

Results

The coadministration of CQ + TQ had no effect on TQ AUC_0–t, AUC_0–∞, T_max or t_1/2. The 90% confidence intervals of CQ + TQ vs. TQ for AUC_0–t, AUC_0–∞ and t_1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ C_max and AUC_0–24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated.

Conclusions

No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.     

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

Aim:

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.

Methods:

A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m², po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, T_max, t_1/2, AUC_0–t, and AUC_0–∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and C_max of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.

Results:

The mean values of C_max, AUC_0–t, and AUC_0–∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of C_max, AUC_0–t, and AUC_0–∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.

Conclusion:

The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m²) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.     

Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

AIMS

To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5–30 mg ml⁻¹) complexed with cyclodextrin.

METHODS

An open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test.

RESULTS

Mean bioavailability of midazolam after nasal administration ranged from 76 ± 12% to 92 ± 15%. With formulations delivering 1 mg midazolam, mean C_max values between 28.1 ± 9.1 and 30.1 ± 6.6 ng ml⁻¹ were reached after 9.4 ± 3.2–11.3 ± 4.4 min. With formulations delivering 3 mg midazolam, mean C_max values were between 68.9 ± 19.8 and 80.6 ± 15.2 ng ml⁻¹ after 7.2 ± 0.7–13.0 ± 4.3 min. Chitosan significantly increased C_max and reduced t_max of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1′-hydroxymidazolam were between 0.97 ± 0.15 and 1.06 ± 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 ± 78 ms and 19 ± 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa.

CONCLUSIONS

Effective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMβCD combined with the absorption enhancer chitosan.     

Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects

Background and the purpose of the study

The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated.

Methods

The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC_0–72, AUC_0–8, C_max and T_max. Similarity factor, dissolution efficiency (DE), and mean dissolution time (MDT) was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT) or fraction of the drug dissolved (FRD) vs fraction of the drug absorbed (FRA).

Results

Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC_0–8, and C_max of each two formulations in each bioequivalence studies were within the acceptable range of 80–125%. Differences were not observed between the untransformed T_max values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50) did not reflect their in vivo properties.

Major conclusions

Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in-process quality control of amiodarone tablet formulations.     

The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

AIMS

This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.

METHODS

Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.

RESULTS

Sildenafil exposure was slightly higher [AUC_∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E_max+) and maximum negative (E_max–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.

CONCLUSION

The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.     

Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin

AIMS

This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.

METHODS

This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of dabigatran etexilate on days 9, 16 and 23.

RESULTS

Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC_0–∞) and maximal plasma concentration (C_max) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC_0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for C_max, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC_0–∞ and C_max of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.

CONCLUSIONS

Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.     

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Background and purpose:

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.

Experimental approach:

The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg⁻¹·min⁻¹) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.

Key results:

Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC_last and AUC_inf between both formulations were acceptable for bioequivalence, whereas that of C_max was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E₀ (baseline ApEn)–E_max (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V₁ of both formulations and sex for k₂₁ of microemulsion propofol. The blood-brain equilibration rate constants (k_e0, min⁻¹) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.

Conclusions and implications:

Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.     

Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil

AIMS

The aim was to compare possible effects of verapamil, as a P-glycoprotein (P-gp) inhibitor, on the pharmacokinetics of each fexofenadine enantiomer, as a P-gp substrate.

METHODS

Thirteen healthy Japanese volunteers (10 male and three female) were enrolled. In a randomized, two-phase, crossover design, verapamil was dosed 80 mg three times daily (with total daily doses of 240 mg) for 6 days, and on day 6, a single 120-mg dose of fexofenadine was administered along with an 80-mg dose of verapamil. Subsequently, fexofenadine was administered alone after a 2-week wash-out period. The plasma concentrations of fexofenadine enantiomers were measured up to 24 h after dosing.

RESULTS

During the control phase, the mean AUC_0–∞ of S(−)- and R(+)-fexofenadine was 700 ng h^–1 ml^–1[95% confidence interval (CI) 577, 823] and 1202 ng h^–1 ml^–1 (95% CI 1007, 1396), respectively, with a significant difference (P < 0.001). Verapamil had a greater effect on the pharmacokinetic parameters of S(−)-fexofenadine compared with those of the R(+)-enantiomer, and increased AUC_0–∞ of S(−)-fexofenadine and R(+)-fexofenadine by 3.5-fold (95% CI of differences 1.9, 5.1; P < 0.001) and by 2.2-fold (95% CI of differences 1.7, 3.0; P < 0.001), respectively. The R/S ratio for the AUC_0–∞ was reduced from 1.76 to 1.32 (P < 0.001) by verapamil treatments.

CONCLUSION

This study indicates that P-gp plays a key role in the stereoselectivity of fexofenadine pharmacokinetics, since the pharmacokinetics of fexofenadine enantiomers were altered by the P-gp inhibitor verapamil, and this effect was greater for S-fexofenadine compared with R-fexofenadine.     

Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir

AIMS

To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir.

METHODS

In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1–3 raltegravir 400 mg q12h, days 4–5 washout, days 6–11 maraviroc 300 mg q12h, and days 12–14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.

RESULTS

For maraviroc, the test/reference % ratio (95% CI) for AUC_τ was 85.8 (78.7, 93.5), for C_max was 79.5 (64.8, 97.5) and for C_min was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC_τ was 63.3 (41.0, 97.6), for C_max was 66.8 (37.1, 120.0) and for C_min was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC_τ divided by 12) were >100 ng ml⁻¹, the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C_min decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.

CONCLUSIONS

Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.     

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects

AIMS

To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity.

METHODS

Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C_max of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated.

RESULTS

During the steady-state of rifampicin, the AUC_0–∞ of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C_max by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC_0–∞ decreased by 56% (0.44; CI 0.36, 0.55); C_max increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48).

CONCLUSIONS

Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.     

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers

AIMS

To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy.

METHODS

The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation–estimation method.

RESULTS

The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h⁻¹ (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h⁻¹ (RSE 16.9%) and absorption rate constant 0.758 h⁻¹ (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)^1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC_0–t.

CONCLUSIONS

The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC_0–t was developed from the final model and can be used routinely to optimize individual dosing.     

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A,for the treatment of Alzheimer's disease

Aim:

Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.

Methods:

This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, AUC_{0–72 h} and AUC_0–∞ were calculated. Tolerance assessments were conducted throughout the study.

Results:

ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t_max of huperzine A was 0.76–0.82 h; the AUC_{0–72 h} and C_max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.

Conclusion:

ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.     

Pharmacokinetic comparison of inhaled fixed combination vs. the free combination of beclomethasone and formoterol pMDIs in asthmatic children

Aim

The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.

Methods

Children aged 5–11 years old inhaled BDP 200 μg and formoterol 24 μg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, C_max, t_max, t_1/2). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored.

Results

Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml⁻¹ h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml⁻¹ h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related.

Conclusion

BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5–11-year-old asthmatic children.     

Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer

AIM

To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK).

METHODS

An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 µm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 µg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K⁺) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min.

RESULTS

The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose–response or difference in T : R ratio was noted for OUCC. Fall in K⁺ revealed a significant dose–response with a non-significant T : R ratio.

CONCLUSIONS

The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 µg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.     

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

AIM

To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg.

METHODS

In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2–4) (period 1), oral contraceptive (q24 h, days 12–32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58–60) and oral contraceptive (q24 h, days 40–60) (period 3).

RESULTS

Voriconazole geometric mean AUC_τ and C_max increased 46% (12 682–18 495 ng h ml⁻¹; 90% confidence interval [CI] 32, 61) and 14% (2485–2840 ng ml⁻¹; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC_τ and C_max increased 61% (1031–1657 ng h ml⁻¹; 90% CI 50, 72) and 36% (119–161 ng ml⁻¹; 90% CI 28, 45), respectively, and norethindrone geometric mean AUC_τ and C_max increased 53% (116–177 ng h ml⁻¹; 90% CI 44, 64) and 15% (18–20 ng ml⁻¹; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE.

CONCLUSIONS

Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.
• Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.
• Because co-administration of voriconazole and Ortho-Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs.

WHAT THIS STUDY ADDS

• Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated.
• It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications.