Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants.

Elezanumab is a fully human monoclonal antibody, which is directed against repulsive guidance molecule A. The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab were assessed in 2 Phase 1 clinical studies. The objective of this study was to assess the PK, safety, tolerability, and immunogenicity following intravenous infusion of elezanumab in healthy adult Japanese, Han Chinese, and Caucasian participants as well as Western participants from the single-ascending-dose study. Elezanumab exposures were approximately 20% higher in Japanese and Han Chinese participants compared to White participants without controlling for body weight. After statistically controlling for body weight by including it as a covariate, the PK of elezanumab in White participants were comparable to those in Japanese and Han Chinese participants. The clinical implications of these exposure differences are yet to be determined. All adverse events were assessed by the investigator as having no reasonable possibility of being related to the study drugs and were mild in severity. No positive immunogenicity effect was observed that impacted elezanumab exposure or safety.

Pharmacokinetics, Tolerability, and Safety of Glecaprevir/Pibrentasvir Co-formulated Bilayer Tablet Following Repeated Administration in Healthy Chinese Adults.

Glecaprevir (GLE)/pibrentasvir (PIB) is an all-oral, interferon- and ribavirin-free, pan-genotypic fixed-dose combination regimen approved for the treatment of all major genotypes of hepatitis C virus (HCV) infection in many countries worldwide. To support clinical development in China, an open-label, single-center phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of GLE/PIB in healthy Chinese adults in Mainland China. Eighteen participants received 3 tablets of coformulated GLE/PIB 100/40 mg once daily (QD) for 7 days. Following GLE/PIB 300 mg/120 mg administration, GLE and PIB reached maximum concentration in 4-5 hours with a terminal elimination half-life of 5.9 and 25 hours, respectively. Both GLE and PIB reached steady state by day 5, with no-to-minimal accumulation (≤17% higher). GLE/PIB exposures in healthy Chinese participants were similar to historical observations across phase 1 studies in healthy Western participants. GLE/PIB was safe and well-tolerated, with most adverse events being mild. These pharmacokinetics and safety data, together with existing global efficacy and safety data in healthy and HCV-infected Western participants, support the use of GLE/PIB 300 mg/120 mg QD in adult Chinese patients with chronic HCV infection.

Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

Phase 1 Evaluation of Elezanumab (Anti-Repulsive Guidance Molecule A Monoclonal Antibody) in Healthy and Multiple Sclerosis Participants.

OBJECTIVE: This study was undertaken to describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants. METHODS: The single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50-1,600mg intravenous [IV] and 150mg subcutaneous) in 47 healthy men and women. The multicenter multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1,800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment. RESULTS: No pattern of study drug-related adverse events was identified for either the SAD or MAD elezanumab regimens. Across both studies, the Tmax occurred within 4 hours of elezanumab IV infusion, and the harmonic mean of t1/2 ranged between 18.6 and 67.7 days. Following multiple dosing, elezanumab Cmax , area under the curve, and Ctrough increased dose-proportionally and resulted in dose-dependent increases in elezanumab cerebrospinal fluid (CSF) concentrations. Elezanumab CSF penetration was 0.1% to 0.4% across both studies, with CSF levels of free RGMa decreased by >40%. Changes in CSF interleukin-10 (IL-10) and free RGMa demonstrated dose/exposure-dependence. INTERPRETATION: The elezanumab pharmacokinetic profile supports monthly, or bimonthly, administration of up to 1,800mg with the option of a loading dose of 3,600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1,800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants. ANN NEUROL 2023;93:285-296.

Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2  = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.

Evaluation of Renal Anionic Secretion Following Living-donor and Deceased-donor Renal Transplantation: A Clinical Pharmacokinetic Study of Cefoxitin Microdosing.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. Because kidneys are the primary excretory organs for various drugs/drug metabolites, changes in renal graft function would significantly alter the clearance and exposure of renally secreted drugs. Renal allografts from living and deceased donors normally undergo numerous insults, including injuries associated with prolonged cold ischemic time, reperfusion, and nephrotoxicity due to calcineurin inhibitors. These physiologic and pharmacologic stresses can alter the expression and functional capacity of renal organic anionic transporters (OATs). METHODS: The objectives of this study were to assess the longitudinal changes in renal anionic secretion in kidney transplant patients, to study the effect of prolonged cold ischemic time on OAT secretion in kidney transplant patients (living- versus deceased-donor recipients), and to compare OAT secretory capacity of renal transplant recipients with healthy volunteers. Cefoxitin was used as a probe drug to assess OAT secretion. Cefoxitin pharmacokinetics was studied in 15 de novo renal transplant recipients following intravenous administration of 200 mg cefoxitin within 14 d and beyond 90 d posttransplantation. RESULTS: No longitudinal changes in real OAT secretion in early posttransplant period were observed, and there were no differences in renal OAT secretion between living- and deceased-donor renal transplant recipients. Overall, cefoxitin exposure was 2.6-fold higher and half-life increased by 2.2-fold in renal transplant recipients when compared with historical healthy controls. CONCLUSIONS: These results suggest that OAT system is functioning well, but renal transplant recipients would need significantly lower dosage of drugs that are primarily secreted via the OAT system compared with normal subjects.

Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies- a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

BACKGROUND: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2). METHODS: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised. FINDINGS: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event. INTERPRETATION: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations. FUNDING: AbbVie.

Levodopa-carbidopa intestinal gel high concentration formulation is clinically bioequivalent to commercial formulation.

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax , AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax , AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.

Gestational changes in buprenorphine exposure: A physiologically-based pharmacokinetic analysis.

AIMS: Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy. METHODS: A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study. RESULTS: The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2nd and 3rd trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3rd trimester (-26.3%). CONCLUSION: PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.

A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration.

AIMS: Opioid dependence is associated with high morbidity and mortality. Buprenorphine (BUP) is approved by the Food and Drug Administration to treat opioid dependence. There is a lack of clear consensus on the appropriate dosing of BUP due to interpatient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of the present study was to build and validate robust physiologically based pharmacokinetic (PBPK) models for intravenous (IV) and sublingual (SL) BUP as a first step to optimizing BUP pharmacotherapy. METHODS: BUP-PBPK modelling and simulations were performed using SimCyp® by incorporating the physiochemical properties of BUP, establishing intersystem extrapolation factors-based in vitro-in-vivo extrapolation (IVIVE) methods to extrapolate in vitro enzyme activity data, and using tissue-specific plasma partition coefficient estimations. Published data on IV and SL-BUP in opioid-dependent and non-opioid-dependent patients were used to build the models. Fourteen model-naïve BUP-PK datasets were used for inter- and intrastudy validations. RESULTS: The IV and SL-BUP-PBPK models developed were robust in predicting the multicompartment disposition of BUP over a dosing range of 0.3-32 mg. Predicted plasma concentration-time profiles in virtual patients were consistent with reported data across five single-dose IV, five single-dose SL and four multiple dose SL studies. All PK parameter predictions were within 75-137% of the corresponding observed data. The model developed predicted the brain exposure of BUP to be about four times higher than that of BUP in plasma. CONCLUSION: The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on the varying demographic, physiological and pathological characteristics of patients.

Low vitamin D exposure is associated with higher risk of infection in renal transplant recipients.

BACKGROUND: Vitamin D is a steroid hormone with multiple vital roles within the immune system. Various studies evaluated the influence of vitamin D on infections postrenal transplantation and found contrasting results. This study aimed to assess the relationship between vitamin D status and the incidence of infection in renal transplant recipients. METHODS: This is a retrospective cohort study of adult renal transplant recipients at the University of Pittsburgh Medical Center between 2005 and 2012. Patients were grouped as vitamin D sufficient (≥30 ng/mL) or deficient (<30 ng/mL) based on total serum 25-hydroxyvitamin D concentrations. The association between vitamin D levels collected at any point post-transplantation and incidence of infection within ±90 days of the vitamin D levels were assessed using logistic and Poisson's regression models. RESULTS: Vitamin D sufficiency at any point post-transplantation was significantly associated with a 66% lower odds (OR: 0.34; 95% CI: 0.22-0.52; P<.001) and 43% lower rate of infections (incident rate ratio (IRR): 0.57; 95% CI: 0.46-0.71; P<.001) within ±90 days of the vitamin D level. Baseline vitamin D level was also associated with lower incidence and risk for infections within the first year post-transplantation. CONCLUSION: Adequate levels of vitamin D in kidney transplant recipients are associated with lower infection risk in the first year and at any time post-transplantation.