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Burosumab is indicated for treatment of a rare bone disease, X‐linked hypophosphatemia (XLH). The aim of this analysis was to evaluate the relationship between a treatment response biomarker and patient‐reported outcomes (PROs). Longitudinal data for PROs were obtained from adults with XLH from a phase III study. Individual rich time profiles of the biomarker, serum phosphate were simulated using a prior population pharmacokinetic‐pharmacodynamic model to calculate serum phosphate exposure metrics for each 28‐day treatment cycle, which were then merged with PROs data. Item response theory parameters were first estimated to map a latent variable, ψ, that is, disability score, relative to baseline. Next, the relationships between serum phosphate exposures and ψ were modeled using a nonlinear mixed‐effect (NLME) modeling approach. A combined item response theory–NLME model with average serum phosphate as a predictor of ψ described PROs data well. The model estimates suggested 28%, 31%, and 25% reduction in Western Ontario and McMaster Universities Osteoarthritis Index, brief pain inventory, and brief fatigue inventory scores, respectively, with every unit increase in average serum phosphate from the lower limit of normal (2.5 mg/dL). Additionally, a time effect of ~ 0.08% improvements each week was estimated. The analysis suggested that burosumab treatment‐induced improvements in serum phosphate levels are associated with improvements in PROs in adults with X‐linked hypophosphatemia. The analyses confirmed the importance of prolonged serum phosphate level correction in adult patients with XLH. These results can be useful to guide the design of further studies and to design treatment optimization strategies. [ABSTRACT FROM AUTHOR]

Inclisiran is a novel N‐acetylgalactosamine (GalNAc) conjugated small‐interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half‐life, but long duration of effects on PCSK9 inhibition and low‐density lipoprotein cholesterol (LDL‐C) lowering. The effects on PCSK9 inhibition and consequent LDL‐C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic‐pharmacodynamic (K‐PD) model was developed to characterize inclisiran's dose‐related LDL‐C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL‐C lowering. To accommodate the long duration of action, the K‐PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL‐C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL‐C. The analysis of covariates identified PCSK9 and LDL‐C baseline levels as important factors for the effects of LDL‐C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL‐C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months. [ABSTRACT FROM AUTHOR]

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X‐linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic‐pharmacodynamic (PK‐PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK‐PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first‐order absorption, 1‐compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK‐PD parameters. No other intrinsic factors affected PK or PK‐PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data. [ABSTRACT FROM AUTHOR]

Aims: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI‐0521, a fixed‐dose combination of immediate‐release phentermine (PHEN) and extended‐release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. Materials and methods: This was a multicentre, randomized, double‐blind, parallel‐design, placebo‐controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid‐dose (PHEN/TPM 7.5 mg/46 mg), or a top‐dose (PHEN/TPM 15 mg/92 mg) of VI‐0521. A total of 26 adolescents were included in the PK analysis (14 from the mid‐dose group and 12 from the top‐dose group). Results: On day 56, arithmetic means of terminal elimination half‐life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid‐ and top‐dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was −5.2 mmHg for the placebo group, −2.5 mmHg for the mid‐dose group, and − 5.5 mmHg for the top‐dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was −2.4 mmHg for the placebo group, +3.8 mmHg for the mid‐dose group, and + 2.0 mmHg for the top‐dose group. Participants in the top‐dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid‐dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. Conclusions: Treatment of adolescents with obesity using a fixed‐dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid‐ and top‐dose levels are appropriate for longer‐term safety and efficacy studies in adolescents. [ABSTRACT FROM AUTHOR]

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P <.01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours. [ABSTRACT FROM AUTHOR]

A multi-compartment kinetic model was developed to describe the kinetics of parathion and its metabolites,p-nitrophenol (p-NP) and alkyl phosphates (AP), in order to assess worker exposure and health risks. Model compartments represent body burdens and excreta of parathion and its metabolites; to minimize the number of compartments and free parameters, regrouping was carried out on the basis of the time scales of the kinetic processes involved. Burden variations in time were described mathematically by differential equations that ensure conservation of mass on a mole basis. Model parameter values were determined from statistical fits to published in vivo kinetic data in humans. Except for the dermal absorption fraction and absorption rate, which are known to be subject to wide intra- and inter-individual variability, a single set of parameter values for the internal body kinetics enabled the model to simulate accurately the available kinetic data. For dermal exposure to parathion, with a typical absorption rate of 0.085 h -1 , model simulations show that it takes 20 h to recover half of the total amounts ofp-NP eventually excreted in urine and 30 h for the AP. The model can be used to estimate the dose of parathion absorbed under different exposure routes and temporal scenarios, based on measurements of amounts of metabolites accumulated in urine over given time periods. Using the above dose-excreta links and the human no-observed-effect level for parathion reported in the literature for the inhibition of cholinesterase activities, biological reference values are proposed in the form of specific amounts of urinary metabolites excreted over chosen time periods. [ABSTRACT FROM AUTHOR]

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)