Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole,Rifampicin, Midazolam,and Warfarin in Healthy Adults

Introduction

Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants.

Methods

Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80–1.25.

Results

Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C _max and the area under the plasma concentration–time curve from time zero to infinity (AUC_inf) were 1.30 (90% CI 1.17–1.45) and 2.58 (90% CI 2.32–2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37–0.49) and 0.17 (90% CI 0.15–0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUC_inf and C _max were 0.53 (90% CI 0.47–0.61) and 0.63 (90% CI 0.50–0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C _max increased and mean AUC_inf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits.

Conclusion

These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9.

Funding

Astellas Pharma.

Trial registration

EudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).

     

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster,Amenamevir (ASP2151): Phase 1, Open-Label,Single-Dose,Parallel-Group Studies

Introduction

Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.

Methods

These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.

Results

In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.

Conclusion

The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance

Funding

Astellas Pharma.

     

Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label,Multicenter Study

Introduction

Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.

Methods

In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.

Results

Mean maximum plasma concentration (C_max) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (T_max) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.

Conclusion

Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.

Trial Registration

ClinicalTrials.gov identifier, NCT02451150.

Funding

Takeda Pharmaceutical Co. Ltd.

     

A Pharmacokinetic Bioequivalence Study Comparing Pirfenidone Tablet and Capsule Dosage Forms in Healthy Adult Volunteers

Introduction

Pirfenidone film-coated tablets were developed to offer an alternative to the marketed capsule formulation. This study assessed the bioequivalence of the tablet and capsule formulations under fed and fasted states.

Methods

A Phase I, open-label, randomized, four-treatment-period, four-sequence, crossover pharmacokinetics study (NCT02525484) was conducted. Each subject received an 801-mg single dose of pirfenidone as three 267-mg capsules or one 801-mg tablet under fasted and fed conditions. Pirfenidone plasma C _max, AUC_0–t and AUC_0–∞ were used to assess bioequivalence.

Results

Forty-four subjects were randomized to treatment. The 801-mg tablet in the fasted state met bioequivalence criteria [90% confidence intervals (CI) 80.00–125.00%] for the GLSM ratios of natural log-transformed C _max, AUC_0–t and AUC_0–∞. Under fed conditions, the 801-mg tablet met the bioequivalence criteria for AUC_0–t and AUC_0–∞, but slightly exceeded the bioequivalence criteria for the C _max (90% CI of 108.26–125.60%). The tablet C _max was approximately 17% higher than that of the capsules. In the fed state, the tablet C _max, and both AUC_0–t and AUC_0–∞ were reduced by 39% and 17%, respectively, relative to the fasted state. The tablet and capsules had acceptable tolerability profiles.

Conclusions

The pirfenidone 801-mg tablet met bioequivalence criteria when compared with three 267-mg capsules in the fasted state. The tablet C _max was slightly higher relative to capsules in the fed state, but this is not expected to have a clinically meaningful impact on the benefit–risk profile of pirfenidone.

Funding

This work was supported by F. Hoffmann-La Roche Ltd.

     

Comparison of the Systemic and Local Pharmacokinetics of Clonidine Mucoadhesive Buccal Tablets with Reference Clonidine Oral Tablets in Healthy Volunteers: An Open-Label Randomised Cross-Over Trial

Introduction

The clonidine mucoadhesive buccal tablet (MBT) is a novel delivery system resulting in high and sustained concentrations of clonidine in the oral cavity. In a phase II clinical trial, clonidine MBT reduced the incidence of severe oral mucositis (OM) compared to placebo in head and neck cancer patients undergoing chemoradiation. This study compared the pharmacokinetics (PK), safety and tolerability of clonidine MBT with a reference oral tablet (OT).

Methods

This was a randomised, three-period, single-dose crossover study in 36 healthy subjects aged 18–50 years. Eligibility was assessed within 14 days of the first dose. IMP was administered in the fasted state on day 1 of each treatment period. PK samples were collected up to 24 h (saliva)/96 h (blood) for measurement of the clonidine concentration. Safety and tolerability were evaluated at specified times throughout the study. A washout period of at least 7 days was observed between administrations.

Results

Clonidine MBT (50 and 100 µg) applied to the upper gum resulted in a dose-proportional increase in saliva (C _max and AUC_0–t ) and plasma (C_max and AUC_0–inf) clonidine levels. Clonidine MBT was considered to mimic a continuous release of clonidine in plasma, significantly decreasing the C _max and AUC and increasing the T _max when compared with the reference clonidine HCl tablets. Clonidine MBT exhibited high and prolonged concentrations in saliva where concentrations with the clonidine HCl tablet were negligible. Clonidine MBT exhibited a favourable safety profile with significantly fewer subjects reporting AEs (dry mouth and fatigue) and a reduction in blood pressure when compared to the reference clonidine HCl tablets.

Conclusion

Clonidine MBT is well tolerated and exhibits proportional saliva and plasma PK over the 50–100-µg dose level. The MBT results in higher saliva concentrations and lower systemic exposure than OT, which was associated with a trend towards fewer adverse events and less dry mouth, fatigue and hypotensive effect.

Funding

Onxeo SA.

Trial Registration

ClinicalTrials.gov identifier, NCT02548806.

     

A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice,Water, or Omeprazole in Cystinosis

Introduction

Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR.

Methods

This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences.

Results

All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC_0–t, AUC_0–∞, and C_max were all within the 80–125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated.

Conclusion

Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water).

Funding

Horizon Pharma, Inc.

     

Pharmacokinetics and Safety of Triple Therapy with Vonoprazan,Amoxicillin, and Clarithromycin or Metronidazole: A Phase 1, Open-Label,Randomized, Crossover Study

Introduction

Vonoprazan (TAK-438) is a novel potassium-competitive acid blocker that inhibits gastric H⁺, K⁺-ATPase. The objectives of this study were to evaluate the influence of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole on the pharmacokinetics of each component of the triple therapies (primary) and to evaluate the safety and tolerability of vonoprazan-based triple therapies (secondary) in healthy adults.

Methods

In this single-center, phase 1, open-label, randomized, four-way crossover study, Helicobacter pylori-negative, healthy Japanese male subjects were randomly assigned to 1 of 4 treatment sequences in two cohorts (12 subjects per cohort). Each treatment sequence comprised four treatment periods separated by a washout period of 7 or 14 days. Pharmacokinetic parameters for vonoprazan, amoxicillin, clarithromycin and metronidazole in single therapy or triple therapies were assessed. All adverse events were recorded.

Results

Compared with single therapy, triple therapy with vonoprazan–amoxicillin–clarithromycin increased the area under the plasma concentration–time curve from time 0–12 h (AUC_0-12) and maximum plasma concentration (C _max) of plasma vonoprazan free base by 1.846- and 1.868-fold, respectively, and increased the AUC_0-12 and C _max of plasma clarithromycin by 1.450- and 1.635-fold, respectively. Triple therapy with vonoprazan–amoxicillin–metronidazole had no influence on the pharmacokinetics of vonoprazan or metronidazole. The pharmacokinetics of amoxicillin was not influenced by vonoprazan-based triple therapies. Seven adverse events were reported. Two subjects discontinued because of an adverse event (rash, liver function test abnormal); both events were considered to be study drug-related.

Conclusion

In healthy Japanese male subjects, triple therapy with vonoprazan–amoxicillin–clarithromycin increased vonoprazan and clarithromycin exposure. The safety and tolerability profile of triple therapy with vonoprazan–amoxicillin–clarithromycin or vonoprazan–amoxicillin–metronidazole was favorable in this population.

Funding

Takeda Pharmaceutical Company Ltd.

Trial registration

JapicCTI-153102.

     

A Single-Dose,Crossover-Design Bioequivalence Study Comparing Two Nicotine Gum Formulations in Healthy Subjects

Introduction

Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar-free nicotine gum at corresponding dosages.

Methods

All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2–7 days of washout between treatments. Subjects’ maximal plasma nicotine concentration (C_max) and extent of nicotine absorption (AUC_0–t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for C_max and AUC_0–t were calculated to evaluate bioequivalence between the two products.

Results

Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for C_max and AUC_0–t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated.

Conclusions

A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile.

Funding

GlaxoSmithKline.

Trial Registration

ClinicalTrials.gov identifier NCT01847443.

     

A Randomized Trial Investigating the Pharmacokinetics,Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects

Introduction

Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.

Methods

In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC_0–168h)].

Results

Steady-state exposure of semaglutide was similar for both populations: AUC_0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (C_max) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC_0–168h ERR 1.11; C_max ERR 1.14). Dose-dependent increases in AUC_0–168h and C_max occurred in both populations. Accumulation was as expected, based on the half-life (t_1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.

Conclusions

The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.

Funding

Novo Nordisk A/S, Denmark.

Trial registration

ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

     

Pivotal Bioequivalence Study of Clopacin<Superscript>®</Superscript>, a Generic Formulation of Clopidogrel 75 mg Film-Coated Tablets

Introduction

Clopacin^® (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin^® with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period.

Methods

Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC–MS/MS method. Bioequivalence of Clopacin^® and the reference drug was established by comparison of the primary pharmacokinetic parameters, C _max, AUC_0–t, and AUC_0–∞.

Results

The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64–105.50%, 90.43–111.22%, 88.75–110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin^® and reference drug values for mean time to maximal plasma clopidogrel concentration (t _max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C _max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC_0–t) and extrapolated to infinity (AUC_0–∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%.

Conclusion

This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin^® and the reference originator drug.

Funding

Acino Pharma AG (formerly Cimex AG)

     

Toxicity and Pharmacokinetics of Sustained-Release Dexamethasone in Beagle Dogs

Introduction

The purpose of the present study was to examine the potential ocular and systemic toxicity and toxicokinetics/pharmacokinetics of sustained-release dexamethasone in canines.

Methods

In this non-randomized study, intracanalicular depots (dexamethasone-loaded or placebo vehicle) were inserted into both eyes of 33 beagles. Tear fluid and plasma were collected for toxicokinetic/pharmacokinetic analysis of dexamethasone, ophthalmic examinations were performed for signs of toxicity, and urine and blood samples were collected for urinalysis, hematology, clinical chemistry, and coagulation analysis. Animals were observed daily for signs of toxicity. Macroscopic and microscopic evaluations were performed.

Results

Mean dexamethasone tear fluid concentration from the dexamethasone group decreased from 4245 ng/mL 6-h post-insertion to 1044 ng/mL on Day 35. All plasma dexamethasone levels were below the limit of quantitation. No systemic or ocular toxicities were attributed to the dexamethasone depot.

Conclusion

Sustained-release dexamethasone produced no identifiable ocular or systemic toxicity in this animal model, and pharmacokinetics demonstrated a tapered, sustained drug release.

Funding

Ocular Therapeutix.

     

Pharmacokinetics and Safety of DS-8500a,an Antidiabetic Drug,in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center,Open-Label,Single-Dose Study

Introduction

The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.

Methods

This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.

Results

The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (C_max) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to C_max were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.

Conclusion

DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.

Trial registration

Japic CTI-No. 163135.

Funding

Daiichi Sankyo Co. Ltd., Tokyo, Japan.

     

Single-Dose Comparative Pharmacokinetics of Two Formulations of Lenalidomide 25 mg in Healthy Subjects: A Randomized Crossover Study

Background

Lenalidomide is used for the treatment of multiple myeloma in combination with dexamethasone. The purpose of this study was to compare the pharmacokinetics (PKs) and assess the bioequivalence of two formulations of lenalidomide 25 mg: Lenalid^® 25 mg tablet (test formulation) and Revlimid^® 25 mg capsule (reference formulation).

Methods

A randomized, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 42 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for PK evaluation were collected up to 24 h post-dose and the PK parameters were estimated by non-compartmental methods. Throughout the study, tolerability was assessed on the basis of adverse events, vital signs, and clinical laboratory tests.

Results

The test formulation showed similar PK profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (C_max) was 0.9995 (0.9250–1.0799) and the corresponding value for the area under the concentration–time curve from time zero to time of last quantifiable concentration (AUC_t) was 0.9648 (0.9451–0.9850). Both CIs were within the conventional bioequivalence range of 0.8–1.25. The tolerability profile was not significantly different between the two formulations.

Conclusion

This study found that the PKs of the two formulations of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation.

Funding

Samyang Biopharmaceutical Corp.

     

Pharmacokinetics of digoxin in healthy subjects receiving taranabant,a novel cannabinoid-1 receptor inverse agonist

Introduction

Interaction studies with digoxin (Lanoxin®; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant—a cannabinoid-1 receptor inverse agonist—for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction.

Methods

This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day ?14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued.

Results

The geometric mean ratio and 90% confidence intervals for digoxin AUC_0-∞ were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C_max) were 1.23 (1.09, 1.40). The median time to C_max was the same for both treatments.

Conclusion

Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

     

Pharmacokinetics and safety of single and multiple doses of Asacol tablets in Japanese healthy volunteers

Introduction

The pharmacokinetics and safety of Asacol^® (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn’s disease, were studied in Japanese healthy male volunteers.

Methods

Drug plasma concentrations and urinary and fecal excretions after a single dose (400–4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated.

Results

All adverse events were “not serious.” The peak plasma concentration (C_max) was reached at 12.3–18.0 hours after a single dose, and the C_max and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The C_max and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects.

Conclusions

Asacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.

     

Effects of Ketoconazole on the Pharmacokinetics of Mifepristone,a Competitive Glucocorticoid Receptor Antagonist,in Healthy Men

Introduction

Mifepristone, a competitive glucocorticoid receptor antagonist approved for Cushing syndrome, and ketoconazole, an antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 inhibitor, on mifepristone.

Methods

In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2). Serial pharmacokinetic blood samples were collected predose and over 24 h postdose on days 12 (period 1) and 17 (period 2). A cross-study comparison (using data on file) further examined whether systemic exposure to mifepristone plus ketoconazole exceeded the exposure following mifepristone 1200 mg orally administered for 7 days.

Results

Sixteen subjects were enrolled and 14 completed the study. Concomitant administration with ketoconazole increased the systemic exposure to mifepristone, based on geometric least squares mean ratios, by 28% for C _max and 38% for AUC_0–24. This increase was 85% and 87% of the exposure observed following mifepristone’s highest label dose of 1200 mg/day for C _max and AUC_0–24, respectively. Adverse events (AEs) were reported in 56.3% (9/16) of subjects during administration of mifepristone alone and in 57.1% (8/14) during combination with ketoconazole. No serious AEs were reported.

Conclusion

Systemic exposure to mifepristone increased following multiple doses of mifepristone 600 mg daily plus ketoconazole 200 mg twice daily. Little to no increase in AEs occurred. Dose adjustment of mifepristone may be needed when given with ketoconazole.

Funding

Corcept Therapeutics.

     

Olanzapine vs haloperidol: treating delirium in a critical care setting

Objective

To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to haloperidol in the treatment of delirium in the critical care setting.

Design

Prospective randomized trial

Setting

Tertiary care university affiliated critical care unit.

Patients

All admissions to a medical and surgical intensive care unit with a diagnosis of delirium.

Interventions

Patients were randomized to receive either enteral olanzapine or haloperidol.

Measurements

Patient’s delirium severity and benzodiazepine use were monitored over 5 days after the diagnosis of delirium.

Main results

Delirium Index decreased over time in both groups, as did the administered dose of benzodiazepines. Clinical improvement was similar in both treatment arms. No side effects were noted in the olanzapine group, whereas the use of haloperidol was associated with extrapyramidal side effects.

Conclusions

Olanzapine is a safe alternative to haloperidol in delirious critical care patients, and may be of particular interest in patients in whom haloperidol is contraindicated.

     

Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with severe acute viral bronchiolitis

Objective

To determine the efficacy of nasal continuous positive airway pressure (nCPAP) on respiratory distress symptoms and respiratory effort in young infants with acute respiratory syncytial virus bronchiolitis.

Design

Prospective study.

Setting

The paediatric intensive care unit of a university hospital.

Patients

Twelve infants less than 3 months of age, with severe respiratory distress.

Interventions

Respiratory distress was quantified with a specific scoring system. Oesophageal pressure (Pes) was measured during spontaneous ventilation before and after nCPAP, delivered through an infant-adapted ventilator. Simultaneous recording of gastric pressure (Pgas) was performed in the five oldest patients.

Measurements and results

The respiratory distress score decreased after nCPAP, particularly accessory muscles’ use and expiratory wheezing. The breathing pattern was modified, with shorter inspiratory and longer expiratory time. Pes swings and PTPes_insp, two indices of inspiratory effort, were reduced by 54 (±4)% and 59 (±5)%. PTPgas_exp, an indicator of expiratory muscles activity, was completely abolished. A significant correlation was observed between the respiratory distress score and Pes swings at baseline and after nCPAP.

Conclusions

In young infants with severe acute respiratory syncytial virus bronchiolitis, nCPAP rapidly unloads respiratory muscles and improves respiratory distress symptoms.

     

Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours

Introduction

The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.

Methods

During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.

Results

Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) C_max,ss and AUC_0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean C_max,ss and AUC_0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.

Conclusions

The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.

Funding

AstraZeneca.

Clinical Trial Registration

NCT02093351.

     

Low dose quetiapine induced galactorrhoea: a case report

Background

Quetiapine causes less prolactin elevation and/or galactorrhoea than other atypical antipsychotics.

Case Presentation

Ms AB had galactorrhoea and raised prolactin levels at only 100 mg of quetiapine daily.

Conclusion

Low dose quetiapine can also cause galactorrhoea.