Lu Chen(1), Roger J.M. Brüggemann(2), Yalin Dong(3), Catherijne A.J. Knibbe(1,4), Elke H.J. Krekels(1)
(1) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, The Netherlands; (2) Department of Pharmacy, Radboud University Medical Centre, Radboud University, The Netherlands; (3) Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China; (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Posaconazole is a systemic triazole antifungal drug and mainly indicated for prophylaxis and treatment of invasive yeast and mold infections such as invasive aspergillosis in immunocompromised patients. It was demonstrated that large differences exist in the pharmacokinetic (PK) profile of posaconazole suspension between healthy volunteers and patients and potentially also between patients of different races [1,2]. Our aim is to, for the first time, develop a population PK model of posaconazole oral suspension for Chinese patients. PK parameter values will be compared to PK parameters of Caucasian healthy volunteers and at a later stage also to Caucasian patients.
Methods: 292 posaconazole serum concentrations were obtained from 80 Chinese patients receiving oral suspension for prophylaxis or treatment of invasive fungal diseases. 85% patients had hematological diseases, of which 22.5% patients were diagnosed with acute myelocytic leukemia or myelodysplastic syndromes and 35% received stem cell transplantation. The daily dosage ranged from 200 mg to 900 mg. The blood samples from Chinese patients were obtained during their routine care generally at the end of a dosing interval and only 6.2% samples were collected within 8 h after the last dose. Dense data from 28 Caucasian healthy volunteers (20 receiving 400 BID oral suspension [3] and 8 receiving 300 mg iv single dose [4]) were added to inform the model.
NONMEM 7.3 was used to perform the analysis. A structural and stochastic model was taken from a previous analysis in Caucasian healthy volunteers, which is a two-compartment model with first-order absorption and lag time and first-order elimination with inter-individual variability (IIV) on the central distribution volume, clearance and bioavailability. Different error models were firstly tested for two populations. It was subsequently assessed whether and how the IIV in Chinese patients deviated from healthy volunteers with all structural parameters fixed to those demonstrated in healthy volunteers, based on which the deviation of all structural parameters were assessed. Discrimination between models was made by comparison of the objective function values (OFV) and stratified goodness-of-fit plots. P < 0.01, corresponding to a reduction of 6.64 in the OFV, was considered statistically significant.
Results: A proportional residual error model, stratified by population (Chinese patients and healthy volunteers), was used. The bioavailability in Chinese patients was demonstrated to be approximately 2.5 (95% confidence interval [CI], 1.82 – 4.13) times lower compared to Caucasian healthy volunteers (mean, 18.2% vs. 46.0%). The absolute clearance in Chinese patients was found to be 61.9% (95% CI, 10.5 – 113.3%) higher than in healthy Caucasians (mean value of 9.47 L/h vs. 5.85L/h). A difference in absolute volume of distribution or absorption parameters for Chinese patients could not be identified. IIV was identified for bioavailability and clearance. The IIV for bioavailability and clearance in Chinese patients were almost three (162.3% vs. 50.4%) and two times (48.5% vs. 26.8%) larger than in healthy volunteers, respectively. The proportional residual unexplained variability in Chinese patients was also significantly higher than in healthy volunteers (58.2% vs. 8.1%), which might result from the larger uncertainties in recorded time of drug dosing.
Conclusion: A significantly lower bioavailability with high IIV were demonstrated in Chinese patients in comparison to the Caucasian healthy volunteers, which is expected to be driven by the disease rather than the race, as we hypothesize that various gastric conditions in patients might have worsened the known erratic absorption profile of posaconazole suspension, thereby contributing to the low bioavailability found in Chinese patients. The higher absolute clearance could be driven by either the disease or the race, which we will further investigate in a covariate analysis that aims to identify which patients’ demographic and clinical factors predict the IIV in Chinese patients.
References:
[1] AbuTarif MA et al. Curr Med Res Opin, (2010), 26 (2): 397-405.
[2] Dolton MJ et al. Antimicrob Agents Chemother, (2014), 58 (11): 6879-6885.
[3] Bruggemann RJ et al. J Antimicrob Chemother, (2010), 65 (10): 2188-2194.
[4] Wasmann RE et al. Journal of Antimicrobial Chemotherapy [published online ahead of print] (2020).
Reference: PAGE () Abstr 9437 [www.page-meeting.org/?abstract=9437]
Poster: Drug/Disease Modelling - Infection