Pharmacokinetics of drugs in adult living donor liver transplant patients: regulatory factors and observations based on studies in animals and humans

Li, Mi; Zhao, Yang; Humar, Abhinav; Tevar, Amit D.; Hughes, Christopher J.; Venkataramanan, Raman

doi:10.1517/17425255.2016.1139575

Cited by 17 publications

(10 citation statements)

References 81 publications

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“…Extraction ratio is determined by Qh, intrinsic clearance of drug (CLint) and the fraction of free drug in the blood that flows through the liver (Fu). Any changes in Qh, Fu, and CLint can change the PK of drugs (36). Corticosteroid is commonly used as part of the immunosuppressive regimen after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Venkataramanan

Rivosecchi

et al. 2020

Antimicrob Agents Chemother

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Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (∼53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of ≤0.5 μg/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against <20% of infections caused by Candida albicans and Candida glabrata isolates exhibiting MICs of ≥0.016 and ≥0.5 μg/ml, respectively (modal MICs). These data are consistent with our SOT program’s experience with ISA breakthrough infections, where 3 of 4 were caused by C. glabrata for which probabilities of PK-PD target attainment (PTA) were only 70% and 0% for isolates with MICs of 0.25 μg/ml and 1 μg/ml. Our findings provide important new insights into how ISA use might be optimized following SOT.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Venkataramanan

Rivosecchi

et al. 2020

Antimicrob Agents Chemother

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“…Inflammation is observed during liver regeneration in living-donor liver transplantation and could affect drug metabolism in both donors and recipients ( Li et al, 2016 ). However, no data are currently available to confirm this hypothesis.…”

Section: Pharmacological Consequences Of Inflammation-induced Metabolmentioning

confidence: 99%

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Stanke‐Labesque

Gautier-Veyret

Chhun

et al. 2020

Pharmacology & Therapeutics

122

147

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Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

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“…In addition, many other factors influence the trough levels of the immunosuppressive medication in transplant patients, such as changes in gastric pH, hepatic and bile flow and gastrointestinal motility [12,13]. Some of these confounders have the highest effect in the first phase after transplantation [14]. Since the mean time span between transplantation and DOAC prescription in our cohort was seven years, the effect of these confounders should be limited.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma levels of direct oral anticoagulants, glomerular filtration rate and thrombin generation parameters of patients after solid organ transplantation and in nontransplanted controls. 13 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) 0.257 DOAC, direct oral anticoagulant; SOT, solid organ transplantation; GFR, glomerular filtration rate; LT, lag time; TTP, time to peak; Peak, peak thrombin; ETP, endogenous thrombin potential; VI, velocity index.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of direct oral anticoagulants under long‐term immunosuppressive therapy after liver, kidney and pancreas transplantation

et al. 2021

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Summary The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n = 26), apixaban (n = 20) and edoxaban (n = 1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient‐years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8 ± 29.6% compared to 3.0 ± 16.5% in matched controls (P = 0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.

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Pharmacokinetics of drugs in adult living donor liver transplant patients: regulatory factors and observations based on studies in animals and humans

Cited by 17 publications

References 81 publications

Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Safety and efficacy of direct oral anticoagulants under long‐term immunosuppressive therapy after liver, kidney and pancreas transplantation

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