Impact of mathematical pharmacology on practice and theory: four case studies

Peletier, L. A.; Gabrielsson, Johan

doi:10.1007/s10928-017-9539-8

Cited by 6 publications

(10 citation statements)

References 37 publications

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“…Population PK modeling and simulations were performed in Pumas (version 1.05), 39 a PK/pharmacodynmaic estimation and simulation package in Julia. 40 The first‐order conditional estimation method with interaction (FOCEI) was used to estimate population parameters.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System

Por

Akers

Chung

et al. 2021

The Journal of Clinical Pharma

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Continuous venovenous hemofiltration (CVVH) is a life-sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models. Model qualification was performed with standard diagnostics and comparing predicted PK parameters/time-concentration profiles with those in the existing literature. Monte Carlo simulations were conducted to evaluate the probability of target attainment. A 2-compartment model best described the data. Utilizing albumin as a covariate on volume parameters and leveraging the clearance model from prior literature, our model predicted imipenem central volume and CL within a 10% margin of error across healthy, renally impaired, and burn populations. We provide direct comparison of imipenem CL in burn patients with and without CVVH. Notably, there was no significant difference. Large imipenem V d in patients with severe burns is likely explained by increased capillary permeability, for which serum albumin may be a reasonable surrogate. Dosing 500 mg every 6 hours is adequate for burn patients on renally dosed CVVH; however, suspicion of augmented renal clearance or patients placed on CVVH without renal impairment may necessitate dosing of 1000 mg every 6 hours.

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Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System

Por

Akers

Chung

et al. 2021

The Journal of Clinical Pharma

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“…One-, two-, and three-compartment models were considered to describe revefenacin and THRX-195518 concentration–time data [ 8 ]. The formation rate of THRX-195518 was defined in the model to be a fraction of the clearance rate of revefenacin from the central compartment.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease

Borin

Bourdet

2020

Clin Pharmacokinet

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Background and Objectives Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration–time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies. Methods Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22–700 μg in 935 patients (488 men, 447 women; age 41–88 years) were analyzed using nonlinear mixed-effects modeling. Results Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration–time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518. Conclusions None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease. Registration ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510 Electronic supplementary material The online version of this article (10.1007/s40262-020-00938-3) contains supplementary material, which is available to authorized users.

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“… 30 In this patient group, QTc events resolved after correction of reversible causes such as electrolyte abnormalities. In healthy volunteers without these confounding factors, a thorough QT study with placebo and moxifloxacin controls showed no clinical effect with glasdegib 100 or 200 mg. 31 While this suggests these confounding factors may have increased risk, such factors are likely to be present in many patients in clinical practice.…”

Section: Adding Glasdegib: Our Clinical Experiencementioning

confidence: 99%

Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists

Relias

McBride

Newman

et al. 2020

J Oncol Pharm Pract

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Objective Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC). Data Sources: PubMed and relevant congress abstracts were searched using the term “glasdegib”. In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners. Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39–0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. Conclusions Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

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Impact of mathematical pharmacology on practice and theory: four case studies

Cited by 6 publications

References 37 publications

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease

Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists

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