Katharina Och (1), David Pittrow (2,3), Christiane Johr (4), Christine Pausch (2), Thorsten Lehr (1,5)
(1) Saarmetrics GmbH, Saarbruecken, Germany, (2) Innovation Center Real-World Evidence, GWT-TUD GmbH, Dresden, Germany, (3) Institute for Clinical Pharmacology, Medical Faculty, Technical University Dresden, Dresden, Germany, (4) Mylan Germany GmbH (A Viatris Company), Bad Homburg v. d. Hoehe, Germany, (5) Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Introduction: Certoparin is a low molecular weight heparin (LMWH) with anticoagulative effects which is used for the treatment and prophylaxis of deep vein thrombosis (DVT). Its partial clearance by renal excretion poses the risk of accumulation in patients with renal insufficiency. To gain deeper knowledge of the pharmacokinetics (PK) of certoparin in renally impaired patients, a population PK model has previously been developed based on a mixed study population of healthy and renally impaired individuals [1,2].
Objectives: The aim of this analysis was to evaluate the model performance of the previously developed population PK model of certoparin [1] based on data derived during clinical routine.
Methods: Data from CERT-SRI study [3] – a prospective, open-label, multicenter, non-interventional study – and MEMORY (MEX839) study [2] – an open-label, single center, parallel-group study – were used. The CERT-SRI study included patients with severe renal impairment (eGFR 15-29 ml/min). Certoparin dosing was determined by the attending physician to reach the anti-factor Xa activity (aXa) target range of 0.4-1.1 I.U./ml in plasma. Plasma aXa levels were collected depending on the availability through clinical routine. The MEMORY study comprised renally healthy and renally impaired individuals receiving predefined certoparin regimens (3000 I.U. Q.D./B.I.D., 8000 I.U. Q.D./B.I.D.) over 5 days with aXa measurements in plasma (full profiles) and urine on day 1 and 5. Data from the MEMORY study has already been used for the development of the Certoparin PK model [1]. To evaluate the descriptive performance of the PK model on CERT-SRI data the population (PRED) and individual prediction (IPRED) were compared to the observations visually over time and by goodness-of-fit plots as well as numerically by calculating the mean relative deviation (MRD). To evaluate the predictive performance a visual predictive check (VPC) based on 1000 simulations of the CERT-SRI dataset was done. Additionally, the model parameters were re-estimated using the combined dataset including data from CERT-SRI study and MEMORY study. The analysis was performed using non-linear mixed effects modeling technique implemented in NONMEM version 7.4.3.
Results: Overall, 7 renally impaired patients from CERT-SRI study with 152 dose administrations and 53 plasma levels of aXa as well as 32 individuals from MEMORY study (18 renally impaired and 14 renally healthy individuals) with 750 dose administrations, and 1368 plasma and 282 urine aXa levels contributed to the data set. CERT-SRI patients were all female and their median age was 88 years, median weight was 80 kg and median height was 162 cm. The median age of individuals from the MEMORY study (56.3% female) was 52 years, their median weight was 72 kg, and their median height was 166 cm. External model evaluation proved a good descriptive and predictive performance of the previously developed two-compartment model with first order absorption and clearance divided into a renal and a metabolic clearance process. The model described the plasma aXa levels of all 7 patients well (MRD: 1.2). Empirical Bayes estimates showed no major differences between CERT-SRI and MEMORY. In six out of seven patients, the model predicted the plasma aXa levels accurately. In one patient, the plasma aXa levels were over-predicted. Parameter re-estimation resulted in similar parameter estimates. Using both the original and the re-estimated parameter sets for simulation of two different dosing regimens for renally healthy and renally impaired individuals resulted in comparable plasma aXa-time profiles.
Conclusions: Based on new real-world data the previously developed population PK model of certoparin was externally evaluated and showed good predictive performance. Examining the model within a larger cohort would yield benefits. However, the current findings from this study already demonstrate the model’s capability to describe and predict unknown heterogeneous data.
Funding: This work war part of the CERT-SRI study (DRKS ID DRKS00024758)
References:
[1] Lehr T. A population pharmacokinetic modelling and simulation analysis of certoparin
in subjects with severe renal insufficiency and healthy subjects. Internal pharmacometric report, September 2022.
[2] De Mey C. An open-label, single center, parallel-group study to compare the single and repeated-dose pharmacokinetics of stepwise increasing doses of subcutaneous certoparin (3,000 IU o.d., 3,000 I.U. b.i.d., 8,000 I.U. o.d., and 8,000 I.U. b.i.d.) in subjects with severe renal insufficiency and healthy subjects. Clinical Study Report: MEX-839 Study, June 2013.
[3] Pittrow D. Certoparn 8.000 I.U. in patients with deep vein thrombosis an severe renal insufficiency. Clinical Study Report: CERT-SRI Study, November 2023.
Reference: PAGE 32 (2024) Abstr 11062 [www.page-meeting.org/?abstract=11062]
Poster: Drug/Disease Modelling - Other Topics