The effect of gastrointestinal graft-versus-host disease and diarrhea on the pharmacokinetic profile of sotrovimab in hematopoietic stem cell transplant recipients.

BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics (PK) of the long-acting mAb sotrovimab targeting SARS-CoV-2 in hematopoietic cell transplant (HCT) recipients. METHODS: All participants received an intravenous infusion of sotrovimab within one week prior to initiating the pre-transplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks post-transplant. RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal (GI) graft-versus-host disease (GVHD) post-transplant. CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased GI clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.

Population pharmacokinetic and exposure-response modelling to inform upadacitinib dose selection in adolescent and adult patients with atopic dermatitis.

AIMS: First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure-response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD were evaluated. METHODS: A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationships, and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS. RESULTS: Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration-time curve from time zero to 24 h after dosing (AUC24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8-14%) with the upadacitinib 30 mg once-daily regimen compared to 15 mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models. CONCLUSION: The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.

A rare case of methotrexate and primaquine co-administration in a mantle cell lymphoma patient.

WHAT IS KNOWN AND OBJECTIVE: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. CASE SUMMARY: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. WHAT IS NEW AND CONCLUSION: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.

Efficacy of photodynamic therapy in the treatment of symptomatic oral lichen planus: A systematic review.

BACKGROUND: The aim of this study was to systematically review the efficacy of photodynamic therapy (PDT) in the management of symptomatic oral lichen planus (OLP). MATERIALS AND METHODS: PubMed/MEDLINE, Scopus, and ISI Web of knowledge were searched until July 2017, using the following keywords: OLP, erosive lichen planus, lichen planus, and PDT. RESULTS: Five clinical studies were included. The risk of bias was considered high in 4 studies and moderate in 1 study. The efficacy of PDT was compared with topical corticosteroids in all included studies. Laser wavelengths, duration of irradiation, and power density ranged between 420-660 nm, 30 seconds to 10 minutes, and 10-500 mW/cm2 , respectively. All studies reported PDT to be effective in the management of symptomatic OLP. Two studies reported PDT to be as effective as corticosteroids, 1 study reported a better efficacy of PDT compared to corticosteroids, whereas 2 studies found PDT to be inferior to corticosteroids. CONCLUSIONS: The limited available evidence suggests that PDT is an effective treatment option for the management of OLP. However, due to the limited number of studies included in this review and heterogeneity among these studies, more well-designed clinical trials with adequate sample sizes are highly warranted.

Efficacy of low-level laser therapy in management of recurrent herpes labialis: a systematic review.

Recurrent herpes labialis (RHL) is a highly prevalent viral infection that affects the oro-facial region. Current treatment options have limited efficacy in reducing healing time and recurrence rate of the disease. Recently, low-level laser therapy has been proposed as a potential treatment alternative for the management of RHL with no side effects. This systematic review aims to evaluate the effectiveness of laser therapy in the management and prevention of RHL. A comprehensive search of Medline/PubMed, Scopus, and Web of Science was carried out to identify published clinical trials comparing laser intervention to active and/or non-active controls for the treatment of RHL. Due to marked heterogeneity of available data, studies were assessed qualitatively, and no statistical analysis was performed. Of the retrieved 227 articles, six clinical trials met the eligibility criteria. The wavelengths, the power output, and energy density ranged between 632.5-870 nm, 5-80 W, and 2.04-48 J/cm2, respectively. All included studies found laser to be effective in the management and prevention of RHL, without any side effects. The findings of this review suggest that laser is potentially a safe and effective treatment alternative for the management of RHL. However, due to high variability in study designs and inconsistency in laser parameters among the included studies, more well-designed randomized clinical trials with standardized laser parameters are highly warranted.

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 µg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 µg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Generation of selectable marker-free transgenic eggplant resistant to Alternaria solani using the R/RS site-specific recombination system.

KEY MESSAGE: Marker-free transgenic eggplants, exhibiting enhanced resistance to Alternaria solani , can be generated on plant growth regulators (PGRs)- and antibiotic-free MS medium employing the multi-auto-transformation (MAT) vector, pMAT21 - wasabi defensin , wherein isopentenyl transferase ( ipt ) gene is used as a positive selection marker. ABSTRACT: Use of the selection marker genes conferring antibiotic or herbicide resistance in transgenic plants has been considered a serious problem for environment and the public. Multi-auto-transformation (MAT) vector system has been one of the tools to excise the selection marker gene and produce marker-free transgenic plants. Ipt gene was used as a selection marker gene. Wasabi defensin gene, isolated from Wasabia japonica (a Japanese horseradish which has been a potential source of antimicrobial proteins), was used as a gene of interest. Wasabi defensin gene was cloned from the binary vector, pEKH-WD, to an ipt-type MAT vector, pMAT21, by gateway cloning technology and transferred to Agrobacterium tumefaciens strain EHA105. Infected cotyledon explants of eggplant were cultured on PGRs- and antibiotic-free MS medium. Extreme shooty phenotype/ipt shoots were produced by the explants infected with the pMAT21-wasabi defensin (WD). The same PGRs- and antibiotic-free MS medium was used in subcultures of the ipt shoots. Subsequently, morphologically normal shoots emerged from the Ipt shoots. Molecular analyses of genomic DNA from transgenic plants confirmed the integration of the WD gene and excision of the selection marker (ipt gene). Expression of the WD gene was confirmed by RT-PCR and Northern blot analyses. In vitro whole plant and detached leaf assay of the marker-free transgenic plants exhibited enhanced resistance against Alternaria solani.

Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies.

INTRODUCTION: Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. METHODS: Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. RESULTS: Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. CONCLUSIONS: This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers. METHODS: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections. RESULTS: There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80-125%). Geometric mean Cmax and AUClast following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants. CONCLUSIONS: After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04988152.

Population pharmacokinetics and exposure-response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID-19.

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two-compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across severe acute respiratory syndrome-coronavirus 2 variants.

Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial.

Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Method: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Results: Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Clinical Trials Registration: ClinicalTrials.gov: NCT04913675.

Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women.

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice-daily on days 3-11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5-hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix-omeprazole drug-drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice-daily for 9 days increased omeprazole exposure by 1.8-fold and decreased the metabolite-to-parent ratio for 5-hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite-to-parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2- to 2.5-fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5-hydroxyomeprazole decreased by 20%-30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3-fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19-mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.

BACKGROUND: ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile. METHODS: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705. FINDINGS: Between Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85; p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23; p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44; p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41; p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13; p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups. INTERPRETATION: Significant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib. FUNDING: AbbVie.

Drug-Drug Interaction Studies of Elagolix with Oral and Transdermal Low-Dose Hormonal Add-Back Therapy.

BACKGROUND AND OBJECTIVE: Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-dose hormonal add-back therapy can reduce hypoestrogenic effects associated with elagolix, thus there is a need to determine if there is a pharmacokinetic interaction between elagolix and low-dose hormonal add-back therapy. METHODS: Two multiple-dose, open-label, single-sequence, non-randomized studies for elagolix 300 mg twice daily with oral (n = 24) and transdermal (n = 36) low-dose add-back therapy (estradiol [E2]/norethindrone acetate [NETA]; 1 mg/0.5 mg oral and 0.51 mg/4.8 mg transdermal) in healthy postmenopausal women were conducted, with pharmacokinetic sampling for E2, estrone (E1), and NETA up to 72 or 96 h after dosing. Pharmacokinetic parameters for hormones were estimated using noncompartmental methods. RESULTS: No change in norethindrone maximum plasma concentration or area under the concentration-time curve was observed when oral E2/NETA was administered with elagolix. For E2, there was a 2-fold increase in maximum plasma concentration and a 1.5-fold increase in the area under the concentration-time curve, and for E1 there was a 1.7-fold increase in maximum plasma concentration when oral E2/NETA was administered with elagolix. Exposures for norethindrone, E2, and E1 were unchanged when transdermal E2/NETA was applied with elagolix administration. CONCLUSIONS: Although changes in E2/E1 exposures were observed when oral E2/NETA was co-administered with elagolix, these changes are not considered clinically relevant; and no dose adjustments are recommended when elagolix is co-administered with oral or transdermal low-dose add-back therapy.

Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis.

Elagolix is a novel, oral gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose-dependent suppression of estradiol (E2) in clinical studies. A dose-response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen [CTX]), formation (N-terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in -0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus.

BACKGROUND: Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus. METHODS: Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted. RESULTS: Effect of venetoclax plasma exposures on B lymphocytes was described using an indirect linear response model and on total lymphocytes using a maximal response (Emax) with an effect site compartment. Baseline lymphocyte counts were significant covariates on the slope and half maximal inhibitory concentration parameter estimates for the respective models; with higher baseline counts associated with a greater reduction upon treatment with venetoclax. Model simulations showed that continuous dosing with lower doses of venetoclax (e.g., 150 mg daily) are predicted to achieve similar maximal effects on B-lymphocyte counts compared to cyclic dosing with higher doses (e.g., 400 mg 1 week on/3 weeks off); with better recovery of total lymphocyte counts during off-treatment weeks for the cyclic regimens. CONCLUSIONS: Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. CLINICALTRIALS.GOV: NCT01686555.

Effect of Elagolix Exposure on Clinical Efficacy End Points in Phase III Trials in Women With Endometriosis-Associated Pain: An Application of Markov Model.

Elagolix is an oral gonadotropin-releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate-to-severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate-to-severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg ) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed-effects discrete-time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates that the selection of elagolix dose is not determined based on tested patient demographics, baseline, or endometriosis disease severity measures in covariate analysis. In other words, the work suggests no preference of one regimen over the other to treat endometriosis-associated pain (DYS or NMPP) for any patient subpopulation based on tested covariate groups.

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials.

Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2-compartment model with first-order absorption and lag time for the immediate-release formulation and mixed zero- and first-order absorption with lag time for the extended-release formulation, and linear elimination adequately described upadacitinib plasma concentration-time profiles. The oral bioavailability of upadacitinib extended-release formulation was estimated to be approximately 80% relative to the immediate-release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady-state area under the plasma concentration-time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady-state AUC, while subjects with rheumatoid arthritis had 35% higher steady-state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady-state exposures.

Exposure-Safety Analyses Identify Predictors of Change in Bone Mineral Density and Support Elagolix Labeling for Endometriosis-Associated Pain.

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose-dependent manner. It is indicated for management of moderate-to-severe pain associated with endometriosis. A population exposure-response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis-associated pain. Elagolix pharmacokinetic exposure-dependent changes in BMD were described by an indirect-response maximum effect (Emax ) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type-I collagen C-telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in -1.45% (-2.04 to -0.814) decrease from baseline in BMD and were used to support corresponding dosing recommendations in the label.

Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis.

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ≤ 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs.