Rujia Xie (1), Susan Raber (2), Robert Swanson (3), Margaret Tawadrous (3), Heidi Leister-Tebbe (3), Ping Liu (4), Lynn McFadyen (5)
(1) Pharmacometrics, Pfizer Inc., Singapore, (2) Clinical Pharmacology, Pfizer Inc., USA, (3) Clinical, Pfizer Inc., USA, (4) Clinical Pharmacology, Linking Truth Technology Co. Ltd., Beijing, China, (6) Pharmacometrics, Pfizer Inc., UK
Objectives: Anidulafungin (ANID) is an intravenous (IV) echinocandin synthesized from a fermentation product of Aspergillus nidulans. ANID is approved for treatment of invasive candidiasis including candidemia (ICC) in adult patients worldwide. The approved adult dosing regimen is a 200 mg loading dose (LD) followed by 100 mg maintenance dose (MD) once daily (QD). Previously, the pharmacokinetics (PK) of ANID have been evaluated in healthy adult subjects, subjects with renal or hepatic impairment, subjects with fungal infections, and pediatric subjects aged 2 to 17 years. ANID exhibits linear and predictable PK. The objectives of our analyses were to describe the PK of ANID in pediatric and adult subjects with ICC, to explore the relationships of exposure-efficacy and safety, and to confirm the proposed pediatric dosing regimen is appropriate.
Methods:Four studies (2 adult and one pediatric ICC clinical studies, and one Investigator-Initiated Research (IIR) pediatric PK study conducted by Duke University in neonates and infants) were included in the PK analysis. Adults received a 200 mg LD followed by 100 mg MD QD, and pediatric subjects received a 3 mg/kg (maximum 200 mg) LD followed by 1.5 mg/kg (maximum 100 mg) MD QD.
The 3 clinical studies were included in exposure-efficacy and exposure-safety graphical and logistic regression analyses. ANID exposures (AUC0-24,ss and Cmin,ss) were examined graphically as potential predictors for efficacy endpoints (global response of success/failure and all-cause mortality) and incidence of all-cause treatment-emergent hepatic and/or gastrointestinal (GI) adverse events (AE) for subjects with PK data. Probability of efficacy outcomes and incidence of AEs were graphically evaluated for 5 AUC0-24,ss quantile groups (quantile <=20%, >20%-40%, >40%-60%, >60%-80%, >80%).
A nonlinear mixed effects modeling approach (NONMEM) was used for the analyses. The estimation methods were first-order conditional estimation method with interaction (FOCEI) for PK and LAPLACE for binary safety data.
Results:One hundred and sixty three subjects (95 males and 68 females) from the 4 studies were included in the PK analysis, in which 14 from the Duke IIR, 66 from the pediatric study, and 83 from the adult studies provided 797 ANID concentrations (391 from pediatric subjects). ANID PK was best characterized by a 2-compartment model with 1st order elimination. Body weight was a covariate on clearance (CL), central volume of distribution (Vc), and peripheral volume of distribution (Vp). No other covariates (eg. age or sex) were identified as statistically significant. A typical subject weighing 70 kg had estimated CL, Vc, Vp, and inter-compartmental clearance (Q) of 1.16 L/h, 26.7 L, 22.4 L, and 2.37 L/h, respectively. The inter-individual variability for CL, Vc, Vp and Q were 37.9%, 46.5%, 53.8% and 52.2%, respectively. Predicted mean AUC0-24,ss (for MD doses) were 80.8, 82.9, 82.8, 86.8, and 91.1 µg*h/mL for neonates, children aged 1 month < 2 years, 2-0-24,ss and Cmin,ss) across the five age groups were comparable. Visual predictive check (VPC) and prediction corrected VPC (pcVPC) plots indicate that in general the final model predicts the data well across the studies, with good match between the median, 5th and 95th percentiles for the observed and simulated data across the age groups.
Probability of treatment failure or death does not appear to be related to low exposures. There appeared to be a trend in relationship between exposure and incidence of all-cause hepatic AEs but not GI AEs. None of the exposure parameters were identified as a statistically significant predictor for the incidence of hepatic or GI AEs.
Conclusions: The proposed IV dosing regimen, a 3.0 mg/kg (maximum 200 mg) LD followed by 1.5 mg/kg (maximum 100 mg) MD QD, is considered appropriate for pediatric patients 1 month to
References:
[1] Liu P, 2013, Population pharmacokinetic-pharmacodynamic analysis of anidulafungin in adult patients with fungal infections. Antimicrob Agents Chemother vol. 57: 466–74.
Reference: PAGE 28 (2019) Abstr 8885 [www.page-meeting.org/?abstract=8885]
Poster: Drug/Disease Modelling - Infection