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Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment. [ABSTRACT FROM AUTHOR]

Background The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. Objectives A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). Methods Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. Results No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean T max range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean T max 3.87 h), a lower C max (−17.7%) and increased AUC0– t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both C max and AUC0–tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0–tau) compared with C max (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. Conclusions Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food. [ABSTRACT FROM AUTHOR]

Momelotinib—approved for treatment of myelofibrosis in adults with anemia—and its major active metabolite, M21, were assessed as drug–drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple‐dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single‐dose rifampin), and a strong CYP3A4 inducer (multiple‐dose rifampin). Momelotinib DDI perpetrator potential (multiple‐dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), time to reach Cmax, and half‐life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single‐dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple‐dose rifampin compared with single‐dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple‐dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1′‐hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short‐term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments. [ABSTRACT FROM AUTHOR]

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics. GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half‐life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound. [ABSTRACT FROM AUTHOR]

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual‐chamber cartridge (DCC) single‐dose pen‐injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2‐period, randomized, crossover, double‐blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen‐injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8‐week washout period between regimens: albiglutide 50‐mg liquid formulation from an auto‐injector and lyophilized placebo from a DCC pen‐injector (Regimen A), or placebo liquid from an auto‐injector and lyophilized albiglutide 50 mg from a DCC pen‐injector (Regimen B). Geometric mean total exposures (area under the drug concentration–time curve [AUC](0‐t) [1345.4 vs 1426.9 (μg · h/mL)], AUC(0‐∞) [1376.2 vs 1454.6 (μg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49‐101.52) for AUC(0‐∞), 95.1% (89.12‐101.49) for AUC(0‐t), and 93.2% (86.76‐100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed. [ABSTRACT FROM AUTHOR]

Background:The 13C-octanoic acid breath test is a convenient method for assessing gastric emptying (GE). Success depends on obtaining a well-characterized time profile of the excretion of label in breath, which may not be the case if GE is delayed. Aims: To use Bayesian techniques in conjunction with hierarchical modelling as a method to increase the success of the modelling process. Methods: Retrospective analysis of 164 individual breath tests using the WinBUGS program. The approach was tested by analysing the complete dataset simultaneously, and also as individual studies. Results: The time required for Bayesian modelling was comparable with that needed for the usual methods. The results obtained were almost identical to those obtained from conventional modelling for well-behaved breath tests, but much more realistic in cases where the experimental data was poor, or when GE was delayed. Conclusions: The use of Bayesian estimation of the parameters of the 13C-octanoic acid breath test is demonstrated. By adopting a hierarchical model, realistic values for the lag phase and half-emptying time were obtained in situations when conventional parameter estimation failed. This is particularly relevant when GE is unexpectedly delayed. We recommend that WinBUGS become the method of choice for analysing breath test data. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (C max ), area under the concentration-time curve (AUC), time to reach C max , and half-life. The increase in momelotinib (23% C max , 14% AUC) or M21 (30% C max , 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% C max , 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% C max , 46% AUC) and increase in M21 (31% C max , 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (C max no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% C max , 16% AUC decreases) or 1'-hydroxymidazolam (14% C max , 16% AUC decreases) but increased rosuvastatin C max by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, but offer less mechanistic insights. The opportunity of using ML predictions of drug PK as input for a PKPD model could strongly accelerate analysis efforts. Here exemplified by rifampicin, a widely used antibiotic, we explore the ability of different ML algorithms to predict drug PK. Based on simulated data, we trained linear regressions (LASSO), Gradient Boosting Machines, XGBoost and Random Forest to predict the plasma concentration-time series and rifampicin area under the concentration-versus-time curve from 0-24 h (AUC 0-24h ) after repeated dosing. XGBoost performed best for prediction of the entire PK series ( R 2 : 0.84, root mean square error (RMSE): 6.9 mg/L, mean absolute error (MAE): 4.0 mg/L) for the scenario with the largest data size. For AUC 0-24h prediction, LASSO showed the highest performance ( R 2 : 0.97, RMSE: 29.1 h·mg/L, MAE: 18.8 h·mg/L). Increasing the number of plasma concentrations per patient (0, 2 or 6 concentrations per occasion) improved model performance. For example, for AUC 0-24h prediction using LASSO, the R 2 was 0.41, 0.69 and 0.97 when using predictors only (no plasma concentrations), 2 or 6 plasma concentrations per occasion as input, respectively. Run times for the ML models ranged from 1.0 s to 8 min, while the run time for the PM model was more than 3 h. Furthermore, building a PM model is more time- and labor-intensive compared with ML. ML predictions of drug PK could thus be used as input into a PKPD model, enabling time-efficient analysis.

Background: The (13)C-octanoic acid breath test is a convenient method for assessing gastric emptying (GE). Success depends on obtaining a well-characterized time profile of the excretion of label in breath, which may not be the case if GE is delayed., Aims: To use Bayesian techniques in conjunction with hierarchical modelling as a method to increase the success of the modelling process., Methods: Retrospective analysis of 164 individual breath tests using the WinBUGS program. The approach was tested by analysing the complete dataset simultaneously, and also as individual studies., Results: The time required for Bayesian modelling was comparable with that needed for the usual methods. The results obtained were almost identical to those obtained from conventional modelling for well-behaved breath tests, but much more realistic in cases where the experimental data was poor, or when GE was delayed., Conclusions: The use of Bayesian estimation of the parameters of the (13)C-octanoic acid breath test is demonstrated. By adopting a hierarchical model, realistic values for the lag phase and half-emptying time were obtained in situations when conventional parameter estimation failed. This is particularly relevant when GE is unexpectedly delayed. We recommend that WinBUGS become the method of choice for analysing breath test data., (Copyright © 2010 S. Karger AG, Basel.)