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Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment
J Clin Pharmacol. 2024 Mar 22. doi: 10.1002/jcph.2427. Online ahead of print.ABSTRACTFirsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stab...
Source: The Journal of Clinical Pharmacology - March 23, 2024 Category: Drugs & Pharmacology Authors: Islam R Younis Cara Nelson Elijah J Weber Ann R Qin Timothy R Watkins Ahmed A Othman Source Type: research

Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment
J Clin Pharmacol. 2024 Mar 22. doi: 10.1002/jcph.2427. Online ahead of print.ABSTRACTFirsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stab...
Source: The Journal of Clinical Pharmacology - March 23, 2024 Category: Drugs & Pharmacology Authors: Islam R Younis Cara Nelson Elijah J Weber Ann R Qin Timothy R Watkins Ahmed A Othman Source Type: research

First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants
J Clin Pharmacol. 2024 Mar 21. doi: 10.1002/jcph.2432. Online ahead of print.ABSTRACTPathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia...
Source: The Journal of Clinical Pharmacology - March 22, 2024 Category: Drugs & Pharmacology Authors: Natasha Novikov Akshay Buch Hua Yang Michelle Andruk Guowen Liu Min Wu Haley Howell Brian MacDonald Will Savage Source Type: research

First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants
J Clin Pharmacol. 2024 Mar 21. doi: 10.1002/jcph.2432. Online ahead of print.ABSTRACTPathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia...
Source: The Journal of Clinical Pharmacology - March 22, 2024 Category: Drugs & Pharmacology Authors: Natasha Novikov Akshay Buch Hua Yang Michelle Andruk Guowen Liu Min Wu Haley Howell Brian MacDonald Will Savage Source Type: research

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation
This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3 mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Katie B Olney Joel I Howard David S Burgess Source Type: research

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2428. Online ahead of print.ABSTRACTUnderstanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of t...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Marion Anliker-Ort Fr édérique Rodieux Victoria C Ziesenitz Andrew Atkinson Julia A Bielicki Thomas O Erb Nicolas G ürtler Stefan Holland-Cunz Urs Duthaler Deborah Rudin Manuel Haschke John van den Anker Marc Pfister Verena Gotta Source Type: research

Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2430. Online ahead of print.ABSTRACTEltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was us...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Wei Zhang Li-Xian Chang Bei-Bei Zhao Yi Zheng Dan-Dan Shan Bo-Hao Tang Fan Yang Yue Zhou Guo-Xiang Hao Ya-Hui Zhang van den Anker John Xiao-Fan Zhu Li Zhang Wei Zhao Source Type: research

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation
This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3 mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Katie B Olney Joel I Howard David S Burgess Source Type: research

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2428. Online ahead of print.ABSTRACTUnderstanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of t...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Marion Anliker-Ort Fr édérique Rodieux Victoria C Ziesenitz Andrew Atkinson Julia A Bielicki Thomas O Erb Nicolas G ürtler Stefan Holland-Cunz Urs Duthaler Deborah Rudin Manuel Haschke John van den Anker Marc Pfister Verena Gotta Source Type: research

Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2430. Online ahead of print.ABSTRACTEltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was us...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Wei Zhang Li-Xian Chang Bei-Bei Zhao Yi Zheng Dan-Dan Shan Bo-Hao Tang Fan Yang Yue Zhou Guo-Xiang Hao Ya-Hui Zhang van den Anker John Xiao-Fan Zhu Li Zhang Wei Zhao Source Type: research

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation
This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3 mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Katie B Olney Joel I Howard David S Burgess Source Type: research

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2428. Online ahead of print.ABSTRACTUnderstanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of t...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Marion Anliker-Ort Fr édérique Rodieux Victoria C Ziesenitz Andrew Atkinson Julia A Bielicki Thomas O Erb Nicolas G ürtler Stefan Holland-Cunz Urs Duthaler Deborah Rudin Manuel Haschke John van den Anker Marc Pfister Verena Gotta Source Type: research

Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2430. Online ahead of print.ABSTRACTEltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was us...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Wei Zhang Li-Xian Chang Bei-Bei Zhao Yi Zheng Dan-Dan Shan Bo-Hao Tang Fan Yang Yue Zhou Guo-Xiang Hao Ya-Hui Zhang van den Anker John Xiao-Fan Zhu Li Zhang Wei Zhao Source Type: research

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation
This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3 mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Katie B Olney Joel I Howard David S Burgess Source Type: research

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study
J Clin Pharmacol. 2024 Mar 18. doi: 10.1002/jcph.2428. Online ahead of print.ABSTRACTUnderstanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of t...
Source: The Journal of Clinical Pharmacology - March 18, 2024 Category: Drugs & Pharmacology Authors: Marion Anliker-Ort Fr édérique Rodieux Victoria C Ziesenitz Andrew Atkinson Julia A Bielicki Thomas O Erb Nicolas G ürtler Stefan Holland-Cunz Urs Duthaler Deborah Rudin Manuel Haschke John van den Anker Marc Pfister Verena Gotta Source Type: research