Zoe Kane (1), Iek Cheng (1), Orlagh McGarrity (2), Robert Chiesa (3), Nigel Klein(4), Mario Cortina-Borja (1), Joseph Standing (1), Silke Gastine (1).
(1) Great Ormond Street Institute of Child Health, University College London, London, UK (2) Pharmacy, Evelina London Children’s Hospital, London, UK (3) University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London,United Kingdom (4) Department of Infection, Immunity and Inflammation, University College London Great Ormond Street Institute of Child Health, London, United Kingdom
Objectives:
Invasive fungal infections (IFIs) are a major cause of morbidity and mortality for immunocompromised patients undergoing both solid organ and stem cell transplantation. Posaconazole is approved for treatment and prophylaxis in adult patients with an injection, oral suspension and gastro-resistant/delayed-released tablet available. However in children posaconazole is used off license and there is an urgent need for greater understanding of posaconazole pharmacokinetics (PK) in this special population.
Posaconazole is lipophilic (logP=4.6), dibasic, poorly soluble and highly plasma protein bound [1]. Posaconazole ADME properties are complex [2,3] and PK after IV dose escalation (50 – 300mg) in healthy adults follows bi-exponential distribution and elimination, with saturable clearance [4].
Here we present model based analysis of real-world posaconazole therapeutic drug monitoring (TDM) data to evaluate simultaneously the bioavailability (F) of the different oral posaconazole formulations typically used in children.
Methods:
A retrospective analysis of posaconazole TDM levels, dose history and patient covariate data captured by a single specialist paediatric hospitals EHRs between Jan 2017 and Aug 2021 has been performed.
Population PK Modelling was performed using NONMEM 7.3 with the FOCEI algorithm. Both 1 and 2 compartmental structural models with linear and non-linear clearance were evaluated. Covariate effects were evaluated for dose, alanine aminotransferase (ALT), Albumin (ALB), diarrhoea and PPI dosing. BLOQ plasma levels were handled using the M3 method.
Results:
298 plasma levels (10 to 11,400 ng/L) from 104 children were included in this analysis. Median age is 6.2 years (IQR 2.6 to 10.6 years) and median weight is 19.5 kg (range 4.3 to 86 kg). The relative proportion of IV:tablet:suspension data is 16:14:70. 69% of the plasma levels were collected during periods of PPI administration and 49% of levels during a period of diarrhoea. 6% of levels were reported as BLOQ.
Modelling of the IV dose escalation PK data published by Kersemaekers et al [4] showed that a saturable clearance model is preferable for posaconazole (-deltaOFV = 35 for 1df) and the CLsat and Km were estimated to be 12 L/hr (RSE 4.3%), 0.5 mg/L (RSE 13.2%) (BMI range from 19 to 35 kg/m^2).
Given the age of our cohort we assumed maturation of the transporters and enzymes responsible for posaconazole elimination to be complete so we fixed distribution, clearance and absorption rate terms based on prior information [4,5,6]. Our final model is a 1-comparment model with 1st order absorption, saturable clearance and additive plus proportional residual error. With a linear clearance model we found that the tablet F tended to estimate as >1, something reported in other, albeit pre-clinical, IV/tablet crossover studies [7].
The covariates that were still found to be significant after backward elimination (p<0.01) were dose and concommitant use of PPIs on suspension F (p=3.7×10-9 and p=0.003) and ALT on CLsat (p=0.006). Diarrhea on suspension F and dose on tablet F were significant (p<0.05) on univariate forward selection (p=0.02 and 0.009 respectively) but then dropped out on backward elimination.
Tablet F is estimated to be 0.80 (RSE 21.2%) and is dose independent with suspension F reducing as dose is increased. The dose at which suspension F is estimate to be 0.5 is 39.0 mg/BSA (RSE 13.9%). IIV on CL is estimated to be 48% (RSE 34.4%, shrinkage 25.0%) while IIV on V has been included in the model it has been fixed to 71% as the data did not support a stable estimate. Additive and proportional error are estimated to be 0.41 mg/L (RSE 57.5%) and 43% (RSE 33%) respectivley with shrinkage of the residual error calculated to be 12.3%.
Conclusions:
To the best of our knowledge this is the first population PK study to model posaconazole PK in immunocompromised children following IV, tablet and suspension dosing simultaneously. This model is able to estimate with reasonable precision the differences in F% of the tablet and suspension in children, whilst also incorporating saturable clearance as seen in adults. We are currently using this model alongside published PD targets [8] to evaluate the probability of target attainment in children using typical paediatric dosing regimens (IV, tablet and suspension).
References:
[1] Hens B, Pathak SM, Mitra A, et al. In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation, and Precipitation of Posaconazole. Mol Pharm 2017; 14: 4321–33.
[2] Noxafil prescribing information: https://www.merck.com/product/usa/pi_circulars/n/noxafil/noxafil_pi.pdf
[3] Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48: 3543–51.
[4] Kersemaekers WM, Van Iersel T, Nassander U, et al. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob Agents Chemother 2015; 59: 1246–51.
[5] Boonsathorn S, Cheng I, Kloprogge F, et al. Correction to: Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children (Clinical Pharmacokinetics, (2019), 58, 1, (53-61), 10.1007/s40262-018-0658-1)
[6] Bentley S, Davies J, Gastine S, et al. Clinical pharmacokinetics and dose recommendations for posaconazole gastroresistant tablets in children with cyctic fibrosis. J. Antimicrob Chemother. 2021 Nov 12;76(12):3247-3254.
[7] Kendall J, Papich MG. Posaconazole pharmacokinetics after administration of an intravenous solution, oral suspension, and delayed-release tablet to dogs. Am J Vet Res 2015; 76: 454–9.
[8] Gastine S, Hope W, Hempel G, et al. Pharmacodynamics of posaconazole in experimental invasive pulmonary aspergillosis: Utility of serum galactomannan as a dynamic endpoint of antifungal efficacy. Antimicrob Agents Chemother 2021; 65.
Reference: PAGE 30 (2022) Abstr 10195 [www.page-meeting.org/?abstract=10195]
Poster: Drug/Disease Modelling - Paediatrics