Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

ABSTRACT 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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Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Cardiology in the Young ◽

10.1017/s1047951115000359 ◽

2015 ◽

Vol 26 (2) ◽

pp. 354-362 ◽

Cited By ~ 8

Author(s):

Kevin D. Hill ◽

Mario R. Sampson ◽

Jennifer S. Li ◽

Robert D. Tunks ◽

Scott R. Schulman ◽

...

Keyword(s):

Drug Exposure ◽

Structural Model ◽

Single Ventricle ◽

Heart Defects ◽

Model Development ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Mixed Effect ◽

The Impact

AbstractAimsSildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.MethodsA population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.ResultsThe analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).DiscussionElevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

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Nocardia thailandica Pulmonary Nocardiosis in a Post-Solid Organ Transplant Patient

Journal of Clinical Microbiology ◽

10.1128/jcm.00959-15 ◽

2015 ◽

Vol 53 (11) ◽

pp. 3686-3690 ◽

Cited By ~ 1

Author(s):

Joseph Canterino ◽

Alberto Paniz-Mondolfi ◽

Barbara A. Brown-Elliott ◽

Wilson Vientos ◽

Ravikiran Vasireddy ◽

...

Keyword(s):

Transplant Patient ◽

Organ Transplant ◽

The United States ◽

Solid Organ Transplant ◽

Nocardia Asteroides ◽

Solid Organ ◽

Content Type ◽

Pulmonary Nocardiosis ◽

Solid Organ Transplant Patient ◽

Organ Transplant Patient

Nocardia thailandicais a rare pathogen related toNocardia asteroides,Nocardia neocaledoniensis, andNocardia caishijiensisthat, since its original description in 2004, has only been reported to cause wound and ocular infections in humans. We report a case of pulmonary nocardiosis caused byNocardia thailandicain a 66-year-old solid organ transplant patient from Connecticut, which was identified at the molecular taxonomic level bysecA1analysis, 16S rRNA gene sequencing, and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). To our knowledge, this is the first reported case ofN. thailandicain the United States and the first report of pulmonary infection by this pathogen in the literature.

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Population Pharmacokinetics of Ganciclovir in Solid-Organ Transplant Recipients Receiving Oral Valganciclovir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00836-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 3017-3023 ◽

Cited By ~ 28

Author(s):

N. Perrottet ◽

C. Csajka ◽

M. Pascual ◽

O. Manuel ◽

F. Lamoth ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Therapeutic Drug ◽

Solid Organ ◽

Transplant Recipients ◽

Mixed Effect ◽

Organ Transplant Recipients ◽

Solid Organ Transplant Recipients

ABSTRACT Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V 1 = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.

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