Large-conductance calcium-activated potassium channel haploinsufficiency leads to sensory deficits in the visual system: a case report.

BACKGROUND: Mutations in the genes encoding the large-conductance calcium-activated potassium channel, especially KCNMA1 encoding its α-subunit, have been linked to several neurological features, including intellectual disability or autism. Associated with neurodevelopmental phenotypes, sensory function disturbances are considered to be important clinical features contributing to a variety of behavioral impairments. Large-conductance calcium-activated potassium channels are important in regulating neurotransmission in sensory circuits, including visual pathways. Deficits in visual function can contribute substantially to poor quality of life, while therapeutic approaches aimed at addressing such visual deficits represent opportunities to improve neurocognitive and neurobehavioral outcomes. CASE PRESENTATION: We describe the case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation (46, XY, t [9; 10] [q23;q22]) disrupting the KCNMA1 gene. The visual processing pathway of the subject was evaluated using both electroretinography and visual contrast sensitivity, indicating that both retinal bipolar cell function and contrast discrimination performance were reduced by approximately 60% compared with normative control values. These findings imply a direct link between KCNMA1 gene disruption and visual dysfunction in humans. In addition, the subject reported photophobia but did not exhibit strabismus, nystagmus, or other visual findings on physical examination. CONCLUSIONS: This case study of a subject with large-conductance calcium-activated potassium channel haploinsufficiency and photophobia revealed a visual pathway deficit at least at the retinal level, with diminished retinal light capture likely due to bipolar cell dysfunction and an associated loss of contrast sensitivity. The data suggest that large-conductance calcium-activated potassium channels play an important role in the normal functioning of the visual pathway in humans, and that their disruption may play a role in visual and other sensory system symptomatology in large-conductance calcium-activated potassium channelopathies or conditions where disruption of large-conductance calcium-activated potassium channel function is a relevant feature of the pathophysiology, such as fragile X syndrome. This work suggests that the combined use of physiological (electroretinography) and functional (contrast sensitivity) approaches may have utility as a biomarker strategy for identifying and characterizing visual processing deficits in individuals with large-conductance calcium-activated potassium channelopathy. Trial registration ID-RCB number 2019-A01015-52, registered 17/05/2019.

Electroretinography and contrast sensitivity, complementary translational biomarkers of sensory deficits in the visual system of individuals with fragile X syndrome.

BACKGROUND: Disturbances in sensory function are an important clinical feature of neurodevelopmental disorders such as fragile X syndrome (FXS). Evidence also directly connects sensory abnormalities with the clinical expression of behavioral impairments in individuals with FXS; thus, positioning sensory function as a potential clinical target for the development of new therapeutics. Using electroretinography (ERG) and contrast sensitivity (CS), we previously reported the presence of sensory deficits in the visual system of the Fmr1-/y genetic mouse model of FXS. The goals of the current study were two-folds: (1) to assess the feasibility of measuring ERG and CS as a biomarker of sensory deficits in individuals with FXS, and (2) to investigate whether the deficits revealed by ERG and CS in Fmr1-/y mice translate to humans with FXS. METHODS: Both ERG and CS were measured in a cohort of male individuals with FXS (n = 20, 18-45 years) and age-matched healthy controls (n = 20, 18-45 years). Under light-adapted conditions, and using both single flash and flicker (repeated train of flashes) stimulation protocols, retinal function was recorded from individual subjects using a portable, handheld, full-field flash ERG device (RETeval®, LKC Technologies Inc., Gaithersburg, MD, USA). CS was assessed in each subject using the LEA SYMBOLS® low-contrast test (Good-Lite, Elgin, IL, USA). RESULTS: Data recording was successfully completed for ERG and assessment of CS in most individuals from both cohorts demonstrating the feasibility of these methods for use in the FXS population. Similar to previously reported findings from the Fmr1-/y genetic mouse model, individuals with FXS were found to exhibit reduced b-wave and flicker amplitude in ERG and an impaired ability to discriminate contrasts compared to healthy controls. CONCLUSIONS: This study demonstrates the feasibility of using ERG and CS for assessing visual deficits in FXS and establishes the translational validity of the Fmr1-/y mice phenotype to individuals with FXS. By including electrophysiological and functional readouts, the results of this study suggest the utility of both ERG and CS (ERG-CS) as complementary translational biomarkers for characterizing sensory abnormalities found in FXS, with potential applications to the clinical development of novel therapeutics that target sensory function abnormalities to treat core symptomatology in FXS. TRIAL REGISTRATION: ID-RCB number 2019-A01015-52 registered on the 17 May 2019.

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.

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 (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 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.

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.

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.

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.

Effect of Multiple Oral Doses of the Potent CYP3A4 Inhibitor Clarithromycin on the Pharmacokinetics of a Single Oral Dose of Vonoprazan: A Phase I, Open-Label, Sequential Design Study.

BACKGROUND AND OBJECTIVES: This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan. METHODS: During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3-9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul). Safety was also assessed. RESULTS: Following administration, vonoprazan was rapidly absorbed (time to reach C max, 2 h), consistent with its known pharmacokinetic profile. This was unchanged in the presence of clarithromycin. Plasma concentrations declined thereafter, with a mean apparent terminal elimination half-life of 7.2 h on day 1 and 9.4 h on day 8. Small-to-moderate increases (1.6- and 1.4-fold) in mean AUC and C max of vonoprazan, respectively, were observed following clarithromycin. In contrast, AUC and C max for vonoprazan metabolites decreased, except for M-IV-Sul, which increased approximately 2.1- and 1.5-fold, respectively. Overall, vonoprazan was well tolerated, with mild or moderate treatment-emergent adverse events occurring in six (37.5%) subjects receiving either vonoprazan and/or clarithromycin. CONCLUSIONS: Modest increases in plasma concentrations of the potent CYP3A4 inhibitor clarithromycin and vonoprazan were observed during coadministration, however these differences were not considered clinically significant. Vonoprazan had a favorable safety and tolerability profile, and no serious adverse events were reported. CLINICALTRIALS.GOV: NCT02774902.

Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers.

RATIONALE: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1). OBJECTIVES: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers. METHODS: The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively. RESULTS: Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg. CONCLUSIONS: The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.

A single-dose PK study of onapristone including the effect of food on absorption.

PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.

Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers.

AIM: The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg(-1) alcohol using 40% vodka). METHODS: In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. RESULTS: Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. CONCLUSION: SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed.

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 Parkinson's 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 50 mg opicapone, 800 mg opicapone, placebo, or 400 mg 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 800 mg 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 800 mg 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 (50 mg) and supratherapeutic (800 mg) doses did not induce a clinically significant prolongation of the QTc interval.

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

BACKGROUND: Many 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. OBJECTIVE: The 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. METHODS: Subjects (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. RESULTS: Healthy 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). CONCLUSIONS: A 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).

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

PURPOSE: Sirolimus 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. METHODS: A 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 4 h 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). RESULTS: The geometric mean ratio and 90 % 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 90 % 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. CONCLUSIONS: The 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.

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.

Antiviral activity of danoprevir (ITMN-191/RG7227) in combination with pegylated interferon α-2a and ribavirin in patients with hepatitis C.

BACKGROUND: Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease. METHODS: The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon α-2a (180 µg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily). RESULTS: Danoprevir in combination with pegylated interferon α-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was -5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and -2.0 log(10) IU/mL (with 3 times daily regimen). CONCLUSIONS: Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon α-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted.

Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study.

BACKGROUND & AIMS: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. METHODS: Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype. CONCLUSIONS: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.

Safety, pharmacokinetic, and pharmacodynamic evaluations of PI-2301, a potent immunomodulator, in a first-in-human, single-ascending-dose study in healthy volunteers.

PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.

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.

A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry-into-man studies: some points to consider from the French Club Phase I working group.

AIM: To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first-entry-into-man (FIM) studies conducted in young healthy subjects. METHODS: A three-level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A 'combined method' based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS: Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS: This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some 'points to consider' helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.