A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children

Abstract

Introduction Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. Methods From 49 pediatric patients (0.7–17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. Results A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5–57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32–2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9–50.3 mg/L*h) on day 1. Conclusion Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting

“…In order to thoroughly investigate the drug-drug interaction, an integrated PK model of dexamethasone and (fos) aprepitant was developed. The PK of (fos)aprepitant was assumed to be described by a one-compartment model with absorption transit compartments, as described by Nijstad et al [28]. The dataset that was used for the current model was previously used for the solely (fos)aprepitant model [28].…”

“…The PK of (fos)aprepitant was assumed to be described by a one-compartment model with absorption transit compartments, as described by Nijstad et al [28]. The dataset that was used for the current model was previously used for the solely (fos)aprepitant model [28].…”

“…Discrimination between models was guided by physiological plausibility, goodness-of-fit (GOF) plots, precision of parameter estimates, and change in objective function value P i = P pop × P (fos)aprepitant cov Table 1 Dose regimens for dexamethasone and (fos) aprepitant BID, twice daily; QD, once daily; QID, four times daily 1 Dexamethasone was administered as commercially available tablets, oral solution, or solution for injection, using locally available products 2 Aprepitant was administered as 80 mg or 125 mg capsules (Merck Sharp & Dohme B.V. [9] or generic equivalent) or as an extemporaneous oral suspension of 10 mg/mL (prepared using the commercially available aprepitant capsule filling and a suspension base as described by Nijstad et al [28]) 3 Fosaprepitant was administered using the commercially available iv fosaprepitant formulation ( (dOFV). A drop of ≥ 3.84 points, corresponding to a P < 0.05 (χ 2 distribution with one degree of freedom (df)), was considered a significant improved fit for hierarchical models.…”