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

UNLABELLED: Aims Sildenafil 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. METHODS: A 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. RESULTS: The 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). Discussion Elevated 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.

Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia.

BACKGROUND: Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated. METHODS: A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions. RESULTS: Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05). CONCLUSIONS: The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.

The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst.

Despite metronidazole's widespread clinical use since the 1960s, the specific enzymes involved in its biotransformation have not been previously identified. Hence, in vitro studies were conducted to identify and characterize the cytochrome P450 enzymes involved in the formation of the major metabolite, 2-hydroxymetronidazole. Formation of 2-hydroxymetronidazole in human liver microsomes was consistent with biphasic, Michaelis-Menten kinetics. Although several cDNA-expressed P450 enzymes catalyzed 2-hydroxymetronidazole formation at a supratherapeutic concentration of metronidazole (2000 µM), at a "therapeutic concentration" of 100 µM only CYPs 2A6, 3A4, 3A5, and 3A7 catalyzed metronidazole 2-hydroxylation at rates substantially greater than control vector, and CYP2A6 catalyzed 2-hydroxymetronidazole formation at rates 6-fold higher than the next most active enzyme. Kinetic studies with these recombinant enzymes revealed that CYP2A6 has a Km = 289 µM which is comparable to the Km for the high-affinity (low-Km) enzyme in human liver microsomes, whereas the Km values for the CYP3A enzymes corresponded with the low-affinity (high-Km) component. The sample-to-sample variation in 2-hydroxymetronidazole formation correlated significantly with CYP2A6 activity (r ≥ 0.970, P < 0.001) at substrate concentrations of 100 and 300 µM. Selective chemical inhibitors of CYP2A6 inhibited metronidazole 2-hydroxylation in a concentration-dependent manner and inhibitory antibodies against CYP2A6 virtually eliminated metronidazole 2-hydroxylation (>99%). Chemical and antibody inhibitors of other P450 enzymes had little or no effect on metronidazole 2-hydroxylation. These results suggest that CYP2A6 is the primary catalyst responsible for the 2-hydroxylation of metronidazole, a reaction that may function as a marker of CYP2A6 activity both in vitro and in vivo.

Considerations and challenges in developing novel long-acting antiretrovirals modalities for treatment and prevention of HIV-1 infection: a regulatory perspective.

PURPOSE OF REVIEW: Outline some regulatory considerations and scientific challenges related to the development of long-acting antiretrovirals (ARVs) for the treatment and prevention of HIV-1 infection. RECENT FINDINGS: Poor adherence to oral ARV regimens continues to pose challenges for effective treatment and prevention of HIV-1 infection. The development of long-acting ARV modalities for treatment and prevention of HIV-1 infection is emerging as a promising alternative to the current treatment and prevention paradigm and has gained considerable interest. SUMMARY: The development of long-acting ARVs can present some unique drug development challenges. Advance planning and prioritization of studies early in development can facilitate the development of long-acting ARVs for the prevention and treatment of HIV-1 infection for all populations, including pediatric patients and pregnant women.

Cobicistat-containing antiretroviral regimens are not recommended during pregnancy: viewpoint.

: Product labels for cobicistat with atazanavir or darunavir, and for elvitegravir/cobicistat/emtricitabine/tenofovir (alafenamide or disoproxil fumarate) were recently updated to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products. Herein, we present the rationale for these recommendations, which are based on studies in pregnant women evaluating the pharmacokinetics and antiviral activity of darunavir/cobicistat or elvitegravir/cobicistat-containing antiretroviral regimens. In these studies, mean steady-state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir were reduced by 61-83%, 89-92%, and 82-86%, respectively. In the absence of data with atazanavir/cobicistat, we leveraged the available data with darunavir/cobicistat and elvitegravir/cobicistat to make recommendations for atazanavir/cobicistat. Darunavir/ritonavir and atazanavir/ritonavir remain viable treatment options for pregnant women.

Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors.

Although current quetiapine labeling recommends that its dosage should be lowered 6-fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions' Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor-quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6-fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors.

Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives.

This review summarizes the significant impact of cytomegalovirus (CMV) infection on solid organ and hematopoietic stem cell transplant recipients. A discussion of the various CMV prevention and treatment strategies is provided, including a detailed description of each of the available CMV antiviral drugs.

Population pharmacokinetics of intravenous acyclovir in preterm and term infants.

BACKGROUND: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. METHODS: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database. RESULTS: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA. CONCLUSIONS: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.

Evidence-based guidelines for pediatric clinical trials: focus on StaR Child Health.

Clinical trials in children are challenging and filled with important ethical considerations that differ from adults. Given difficulties associated with pediatric clinical trials, off-label prescribing is a common practice in pediatrics, which can lead to adverse safety events and efficacy failures. To overcome these consequences, in the past 15 years, legislation in the USA and Europe has provided incentives to industry and increased government funding to conduct pediatric trials. Pediatric trial networks have also been formed to decrease the knowledge gap. However, challenges to performing pediatric trials and lack of standardization and guidelines regarding studies in children still exist. Standards for Research (StaR) in Child Health, begun in 2009, aims to improve the design, conduct and reporting of pediatric trials. This organization uses a consensus guideline approach involving academic, government and industry stakeholders to identify and disseminate best practices for pediatric trials. Six out of 11 planned standards are currently published.