Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants

Abstract

Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (K_I ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUC_ss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUC_ss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.

Figure 1

Sildenafil and N-desmethyl sildenafil (DMS) with and without fluconazole physiologically-based pharmacokinetic model population simulations in preterm infants. Population simulations in 100 preterm infants (33% girls, 7–40 days postnatal age, 24–27 weeks gestational age, and 590–1,242 g) for sildenafil (a) and DMS (b) in infants receiving sildenafil alone, and for sildenafil (c) and DMS (d) in infants receiving sildenafil with steady-state administration of fluconazole for treatment (12 mg/kg i.v. daily) and for sildenafil (e) and DMS (f) in infants receiving sildenafil with fluconazole for prophylaxis (6 mg/kg i.v. every 72 hours). A single dose of 0.25 mg/kg i.v. sildenafil with 6 mg/kg fluconazole i.v. in preterm infants resulted in a simulated mean fold-change of 1.08 for maximal concentration (C_max) and 1.40 for the area under the curve extrapolated to infinity (AUC_0–∞) for sildenafil plus DMS accounting for different phosphodiestesterase type 5 inhibitory activity and protein binding (sildenafil + 0.5*1.25*DMS). A single dose of 0.25 mg/kg i.v. sildenafil with 6 days of fluconazole dosing of 12 mg/kg fluconazole i.v. in preterm infants resulted in a simulated mean fold-change of 1.13 for C_max and 2.59 for AUC_0–∞ for sildenafil plus DMS. The solid grey area is the 95% prediction interval and the dots are concentrations colored by individuals. Results were obtained using the default PK-Sim® ontogeny functions for alpha-1-acid glycoprotein without additional variability introduced on the fraction unbound. Observed concentrations were dose normalized to 0.25 mg/kg.

Figure 2

Results of a sensitivity analysis comparing the influence of cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5), and cytochrome P450 3A7 (CYP3A7) reference concentration on sildenafil AUC_0−∞ after a single oral dose for all ages, except that an i.v. dose was simulated for preterm infants, as a function of age. Comparison of sensitivity values for the impact of reference concentration of CYP3A4 (blue), CYP3A5 (grey), and CYP3A7 (navy) on sildenafil AUC_0–∞ in typical subjects of various ages. A sensitivity analysis was performed for a typical healthy adult, a preterm infant (22 days PNA, 25 weeks GA, and 849 g weight), a term infant at birth (neonate), a term infant at 2 weeks of age, as well as infants, children, and adolescents 1, 2, 3, and 6 months, and 1, 2, 5, and 12 years of age. A sensitivity of −1.0 implies that a 10% increase of CYP3A reference concentration leads to a 10% decrease of AUC_0–∞, and a sensitivity of + 1 implies that a 10% increase of CYP3A reference concentration leads to a 10% increase of AUC_0–∞. AUC_0–∞, area under the plasma concentration vs. time curve from zero to infinity; GA, gestational age; PNA, postnatal age.

Figure 3

Changes in daily AUC_ss and C_max in preterm and term infants receiving modified doses of i.v. sildenafil given t.i.d. in combination with fluconazole compared to preterm and term infants receiving sildenafil alone. Data presented as the geometric mean and associated 90% prediction interval of the change in sildenafil plus 0.5*1.25*DMS (accounting for differences in potency and protein binding) AUC_ss and C_max in infants receiving sildenafil with fluconazole relative to infants receiving sildenafil without fluconazole. The reference sildenafil doses were 0.25 mg/kg i.v., 0.5 mg/kg i.v., or 1 mg/kg i.v., each dose administered over a 90-minute infusion every 8 hours. The fluconazole dose was 12 mg/ kg daily, administered i.v. over a 60-minute infusion. When given in combination with fluconazole, reducing the sildenafil dose by 64% resulted in a geometric mean ratio of 1.01 for AUC_ss, relative to infants receiving sildenafil alone but C_max was underpredicted. To achieve similar C_max values, reducing the sildenafil dose by 48% with fluconazole resulted in a geometric mean ratio for C_max of 0.99 relative to infants receiving sildenafil alone, however, but AUC_ss was overpredicted. AUC_ss, area under the plasma concentration vs. time curve at steady-state; C_max, maximal concentration; CI, confidence interval; DMS, N-desmethylsildenafil; IQR, inter-quartile range.