Alain Patat

Relative Bioavailability of Liquid and Tablet Formulations of the Antiparasitic Moxidectin.

The antiparasitic agent moxidectin is under development for the treatment of onchocerciasis. As the first‐in‐human study of moxidectin used a liquid formulation but other trials used tablets, a study was performed to determine the relative bioavailability of the 2 formulations and to gain more information about the pharmacokinetics of moxidectin. Fifty‐eight healthy male participants were randomized to receive open‐label moxidectin (10 mg) as a tablet (n = 29) or liquid (n = 29) formulation. The mean ± SD pharmacokinetic parameters observed following administration of the tablet were peak concentration (Cmax) 67.1 ± 27.4 ng/mL, time to peak concentration (tmax) 3.2 ± 1.4 hours, area under the concentration time curve (AUC) 4403 ± 2360 ng·h/mL, apparent volume of distribution 3635 ± 1720 L, oral clearance 2.83 ± 1.25 L/h, and elimination half‐life 1032 ± 502 hours. The Cmax and AUC observed following administration of the liquid formulation were 28.6% and 28.8% higher, respectively, and tmax 0.9 hours shorter compared with tablets. No serious adverse events (AEs) were observed. The most commonly reported AEs were headache, infection, diarrhea, asthenia, myalgia, and dizziness during the inpatient phase and flu syndrome, headache, and infection during the 6‐month outpatient phase. There was no difference in reporting of these AEs between formulations.

Pharmacokinetics and Safety of a Single Intravenous Dose of the Antibiotic Tigecycline in Patients With Cirrhosis

Tigecycline belongs to a new class of tetracyclines, the glycylcyclines, less than 20% of which is metabolized in the liver. Twenty‐five patients with cirrhosis with varying degrees of functional hepatic reserve (Child‐Pugh A, n = 10; B, n = 10; C, n = 5) and 23 healthy adults, matched by age, sex, weight, and smoking habits, received 100 mg of tigecycline infused intravenously over 60 minutes. Serum and urine samples were collected up to 120 hours after dosing. Pharmacokinetic data were derived using noncompartmental methods. The most common treatment‐emergent adverse events in healthy volunteers were nausea (56.5%), vomiting (21.7%), and headache (21.7%) and in the patients with cirrhosis, albuminuria (12%). Mean (±1 SD) tigecycline clearance values were 29.8 ± 11.3 L/h in healthy subjects and 31.2 ± 13.9 L/h (Child‐Pugh A), 22.1 ± 9.3 L/h (Child‐Pugh B), and 13.5 ± 2.7 L/h (Child‐Pugh C) in the patients. A single intravenous dose of tigecycline 100 mg was safe and well‐tolerated in patients with cirrhosis with varying degrees of hepatic functional reserve. No adjustment of tigecycline maintenance dosage is warranted in patients with compensated or moderately decompensated cirrhosis; doses should be reduced by 50%, to 25 mg, every 12 hours in patients with severely decompensated disease.

An open-label, single-dose, parallel-group study of the effects of chronic hepatic impairment on the safety and pharmacokinetics of desvenlafaxine.

BACKGROUNDnMany antidepressants are extensively metabolized in the liver, requiring dose adjustments in individuals with hepatic impairment. Clinical studies indicate that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine is metabolized primarily via glucuronidation, and ∼45% is eliminated unchanged in urine.nnnOBJECTIVEnThe objectives of this study were to assess the pharmacokinetic profile, safety, and tolerability of desvenlafaxine in adults with chronic Child-Pugh class A, B, and C hepatic impairment.nnnMETHODSnSubjects (aged 18-65 years) with mild (Child-Pugh class A, n = 8), moderate (Child-Pugh class B, n = 8), and severe (Child-Pugh class C, n = 8) hepatic impairment and 12 healthy matched subjects received a single 100-mg oral dose of desvenlafaxine. Disposition of (R)-, (S)-, and (R+S)-enantiomers of desvenlafaxine were examined in plasma and urine. Geometric least squares (GLS) mean ratios and 90% CIs for AUC, AUC0-τ, Cmax, and Cl/F were calculated; comparisons were made by using a 1-factor ANOVA. Safety was evaluated according to adverse events, physical examination, vital signs, and laboratory assessments.nnnRESULTSnHealthy participants had a mean age of 51 years (range, 36-62 years) and weight of 79.1 kg (range, 52.5-105.0 kg); hepatically impaired participants had a mean age of 52 years (range, 31-65 years) and weight of 80.9 kg (range, 50.2-119.5 kg). In both groups, 67% of participants were male. No statistically significant differences (≥50%) in the disposition of desvenlafaxine were detected between hepatically impaired patients and healthy subjects based on GLS mean ratios for Cmax, AUC0-τ, AUC, or Cl/F (P > 0.05 for each comparison). Median Tmax was similar for all groups (range, 6-9 hours). A nonsignificant increase was observed for desvenlafaxine exposure in patients with moderate or severe hepatic impairment (GLS mean ratios [90% CIs] for AUC, 31% [93.2-184], 35% [96.5-190], respectively). The most common adverse events were nausea (n = 2, healthy subjects; n = 3, hepatically impaired subjects) and vomiting (n = 1, healthy subjects; n = 2, hepatically impaired subjects).nnnCONCLUSIONSnA single 100-mg dose of desvenlafaxine was well tolerated in healthy subjects and hepatically impaired patients. A mild increase in exposure was observed for moderate and severe hepatically impaired subjects (Child-Pugh class B and C).

Evaluation of opicapone on cardiac repolarization in a thorough QT/QTc study

Opicapone, a novel third‐generation catechol‐O‐methyltransferase inhibitor for use as adjunctive therapy in levodopa‐treated Parkinsons disease patients, was investigated on cardiac repolarization in healthy adult volunteers. This was a single‐center, randomized, double‐blind, placebo‐controlled, open‐label active‐controlled, 4‐period crossover study conducted in 64 subjects. In each period, subjects received a single oral dose of 50u2009mg opicapone, 800u2009mg opicapone, placebo, or 400u2009mg moxifloxacin and 24‐hour 12‐lead Holter monitoring was performed on day ‐1 (baseline) and after each single dose. After a single oral administrations of 50 and 800u2009mg opicapone, opicapone was the major entity in the circulation, with a median tmax of 1.5–2.0 hours. Opicapone was rapidly eliminated, with an elimination half‐life of 1–2 hours. There was no clinically relevant effect of 50 and 800u2009mg opicapone versus placebo on cardiac depolarization or repolarization. All upper bounds of the 1‐sided 95% confidence interval (CI) were below 10 milliseconds, confirming that opicapone has no QT‐prolonging effect. Moxifloxacin caused an increase in the QTcI, with a lower bound of the 2‐sided 95% CI always higher than 5 milliseconds, around the tmax of peak concentration, demonstrating assay sensitivity. In conclusion, administration of opicapone at therapeutic (50u2009mg) and supratherapeutic (800u2009mg) doses did not induce a clinically significant prolongation of the QTc interval.

Pharmacokinetics and Safety of Bazedoxifene in Hepatically Impaired and Healthy Postmenopausal Women

Bazedoxifene, a selective estrogen receptor modulator with proestrogenic effects on bone and lipid metabolism and antiestrogenic effects on the breast and endometrium, is a treatment option for osteoporosis in postmenopausal women. It is extensively metabolized by the liver; therefore, a decrease in liver function was expected to decrease bazedoxifene clearance. This single‐dose, open‐label, inpatient/outpatient, nonrandomized study assessed the pharmacokinetics of bazedoxifene 20 mg in 18 postmenopausal women with hepatic impairment and 18 matched healthy postmenopausal women. Bazedoxifene elimination was slower, and exposure was higher, in hepatically impaired subjects compared with healthy subjects. In subjects with severe (Child‐Pugh C) liver impairment, bazedoxifene mean half‐life was 50% longer than that of healthy subjects. Area under the concentration‐time curve geometric mean ratios (90%CI) for Child‐Pugh A, B, and C liver impairment vs healthy subjects were 243% (156‐379), 209% (135‐326), and 368% (236‐572), respectively. Although there were no severe adverse events in this study, bazedoxifene use in patients with hepatic impairment is not recommended.

The evaluation of potential pharmacokinetic interaction between sirolimus and tacrolimus in healthy volunteers

PurposeSirolimus and tacrolimus are immunosuppressive compounds that have been used concomitantly in renal transplant patients. Both drugs are dosed orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. As such, there is a potential for pharmacokinetic drug interaction.MethodsA single-dose, open-label, four-period, four-treatment, randomized crossover study was conducted in 27 healthy fasting volunteers. Each subject received a 15-mg oral dose of sirolimus alone, a 10-mg oral dose of tacrolimus alone, sirolimus and tacrolimus administered simultaneously, and tacrolimus administered 4xa0h before sirolimus. Whole blood and plasma samples for sirolimus and tacrolimus testing were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using noncompartmental methods and were compared using analysis of variance (ANOVA).ResultsThe geometric mean ratio and 90xa0% confidence interval (CI) area under the concentration–time curve from time 0 to infinity (AUCinf) for sirolimus administered simultaneously with tacrolimus versus sirolimus alone were 97 and 89–106, respectively, and, when administered in a staggered approach versus sirolimus alone, 107 and 98–117, respectively. The geometric mean ratio (%) and 90xa0% CI AUCinf for tacrolimus administered simultaneously with sirolimus versus tacrolimus alone were 92 and 82–102, respectively, and, when administered in a staggered approach versus tacrolimus alone, 94 and 84–105, respectively.ConclusionsThe results of this study demonstrate a lack of any clinically important drug interaction between sirolimus and tacrolimus in healthy subjects after single-dose administration. However, due to the complexity of anti-rejection immunosuppressive therapy dosing, we suggest that sirolimus and tacrolimus concentration monitoring be performed when changes in dosing are made for either drug regimen.

Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen

The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45–65 years) received either a single oral dose of ibuprofen (600‐mg tablet), bazedoxifene (20‐mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance. The 90% log‐transformed confidence intervals (CIs) for bazedoxifene Cmax, 96% to 144%, and AUC, 85% to 134%, were slightly above the bioequivalence limits of 80% to 125%. The 90% log‐transformed CIs for ibuprofen pharmacokinetic parameters were within these limits (Cmax, 92%–122%; AUC, 94%–106%). The increase in bazedoxifene plasma concentrations when combined with ibuprofen versus bazedoxifene alone is unlikely to be clinically significant. The lack of interaction between bazedoxifene and ibuprofen suggests that they may be coadministered without dose adjustment.

A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women

An open‐label, 3‐period study was conducted in 30 healthy postmenopausal women (mean age, 58.4 years) who received a single oral dose of atorvastatin 20 mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40 mg on days 4‐11 (period 2), and coadministration of atorvastatin 20 mg + bazedoxifene 40 mg on day 12 (period 3). Serial blood samples were collected (24 hours after bazedoxifene and 72 hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho‐hydroxy and para‐hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20 mg (Cmax and AUCss were within bioequivalence limits). Similarly, atorvastatin and ortho‐hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para‐hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. Cmax for atorvastatin and ortho‐hydroxyatorvastatin was 14% and 18% lower, respectively, and Tmax was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC0‐24 h) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC0‐24 h increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC0‐24 h, whereas odalasvir with/without simeprevir increased ALS‐022227 AUC0‐24 h 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC0‐24 h increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects

Background The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. Methods This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100–1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1−4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. Results Forty-eight HVs and 64 subjects with HCV GT1−4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1−4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0−4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. Conclusions AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1–4-infected subjects, including GT1-infected subjects with cirrhosis.