Population pharmacokinetics of arbekacin in different infectious disease settings and evaluation of dosing regimens

ABSTRACTPractitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

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Population pharmacokinetics of durvalumab and fixed dosing regimens in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2566 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2566-2566 ◽

Cited By ~ 5

Author(s):

Paul Baverel ◽

Vincent Dubois ◽

Chaoyu Jin ◽

Xuyang Song ◽

Xiaoping Jin ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Human Monoclonal Antibody ◽

Fixed Dose ◽

Tumor Type ◽

Disease Characteristics ◽

Relevant Effect ◽

Population Pk ◽

Non Linear ◽

Dosing Regimens ◽

The Impact

2566 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V1) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters < 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562.

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Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model‐Informed Hypothesis Generation for Pediatric Dosing Regimens

The Journal of Clinical Pharmacology ◽

10.1002/jcph.1682 ◽

2020 ◽

Vol 60 (12) ◽

pp. 1585-1597

Author(s):

Ajit Suri ◽

Diane R. Mould ◽

Gregory Song ◽

Judith Kinley ◽

Karthik Venkatakrishnan

Keyword(s):

Population Pharmacokinetics ◽

Pediatric Patients ◽

Hematologic Malignancies ◽

Brentuximab Vedotin ◽

Hypothesis Generation ◽

Dosing Regimens

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Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01265-19 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 10

Author(s):

Fekade B. Sime ◽

Melissa Lassig-Smith ◽

Therese Starr ◽

Janine Stuart ◽

Saurabh Pandey ◽

...

Keyword(s):

Creatinine Clearance ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Rate Constant ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Peripheral Compartment ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Dosing Regimens

ABSTRACT Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean ± standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 ± 3.2 and 25.4 ± 9.4 liters/h, V of 20.4 ± 3.7 and 32.4 ± 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 ± 0.74 and 2.96 ± 8.6 h−1, and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 ± 0.37 and 26.5 ± 8.4 h−1. With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was ≥85% for directed therapy (MIC ≤ 4 mg/liter). However, for empirical coverage (MIC up to 64 mg/liter), the FTA was 84% with the 1.5-g q8h regimen when creatinine clearance is 180 ml/min/1.73 m2, whereas the 3.0-g q8h regimen consistently achieved an FTA of ≥85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT>MIC), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT>MIC is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.

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Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients

British Journal of Clinical Pharmacology ◽

10.1111/bcp.13595 ◽

2018 ◽

Vol 84 (7) ◽

pp. 1587-1597 ◽

Cited By ~ 23

Author(s):

Xiao-bin Lin ◽

Zi-wei Li ◽

Miao Yan ◽

Bi-kui Zhang ◽

Wu Liang ◽

...

Keyword(s):

Renal Transplant ◽

Population Pharmacokinetics ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Dosing Regimens ◽

Cyp2c19 Polymorphisms

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Optimizing gentamicin dosing in different pediatric age groups using population pharmacokinetics and Monte Carlo simulation

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01114-4 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Ragia H. Ghoneim ◽

Abrar K. Thabit ◽

Manar O. Lashkar ◽

Ahmed S. Ali

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Population Pharmacokinetics ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Concentration Data ◽

Once Daily ◽

Dosing Regimens ◽

Gentamicin Concentration

Abstract Introduction The use of once daily dosing of aminoglycosides in pediatrics is increasing but studies on dose optimization targeting the pediatric population are limited. This study aimed to derive a population pharmacokinetic model of gentamicin and apply it to design optimal dosing regimens in pediatrics. Methods Population pharmacokinetics of gentamicin in pediatrics was described from a retrospective chart review of plasma gentamicin concentration data (peak/ trough levels) of pediatric patients (1 month − 12 years), admitted to non-critically ill pediatrics. Monte Carlo simulations were performed on the resulting pharmacokinetic model to assess the probability of achieving a Cmax/MIC target of 10 mg/L over a range of gentamicin MICs of 0.5–2 mg/L and once daily gentamicin dosing regimens. Results: A two-compartment model with additive residual error best described the model with weight incorporated as a significant covariate for both clearance and volume of distribution. Monte Carlo simulations demonstrated a good probability of target attainment even at a MIC of 2 mg/L, where neonates required doses of 6-7 mg/kg/day and older pediatrics required lower daily doses of 4–5 mg/kg/day while maintaining trough gentamicin concentration below the toxicity limit of 1 mg/L. Conclusion: Once daily dosing is a reasonable option in pediatrics that allows target attainment while maintaining trough gentamicin level below the limits of toxicity.

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