Assessment of the nlmixr R-package for population pharmacokinetic modeling: A metformin case study

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

Pharmacokinetic Analysis of a von Willebrand Factor/Factor VIII (VWF/FVIII) Concentrate in Adults and Children with von Willebrand Disease (VWD).

Introduction: Although widely used for the treatment of VWD, optimal doses of VWF/FVIII concentrates for surgical procedures in patients with VWD need to be determined. Two prospective, multicenter studies were undertaken to evaluate the efficacy and safety in surgery of a VWF/FVIII concentrate marketed in the United States (US; Humate-P®) and the European Union (EU; Haemate-P®) in patients with VWD (Lethagen et al. JTH, 2007). Initially, all patients had pharmacokinetic (PK) studies to guide individual dosing for surgery. Results: In the US study, 41 subjects received 60 IU/kg VWF: RCo, and in the EU study 28 subjects received approximately 80 IU/kg VWF: RCo. At specified time points before and after infusion, median levels, half-life, mean change from baseline and in-vivo recovery (IVR) values were determined for VWF: RCo and FVIII: C. Collagen binding capacity (VWF: CB) was correlated with VWF: RCo; and VWF multimer analyses were also performed. In the US and EU studies, median baseline VWF: RCo levels were 13 (range[r] 6–124) and 8.1 (r 5–58) IU/dL; the highest median post-infusion values were 163 (r 84–330) and 147 (r 53–387) IU/dL. Mean change from baseline in the US study was > 100 IU/dL immediately after the infusion, decreasing to about 10 IU/dL at 48 hours post-infusion. The median terminal half-life of VWF:RCo in the US study was 11.7 (r 3.5–74.9) hours. These results are consistent with early and rapid distribution phase, followed by a much slower terminal elimination phase. The median incremental in vivo recovery (IVR) for VWF: RCo in the US and EU studies was 2.4 and 1.9 IU/dL/IU/kg respectively. In the US and EU studies, median baseline levels of FVIII: C were 39 (r 0.5 to 96) and 33 (r 2–106) IU/dL. Mean change of FVIII: C from baseline in the US study was about 60 IU/dL post-infusion, levels decreasing to slightly above 20 IU/dL at 48 hours post-infusion. Median incremental IVRs for FVIII: C in the US and EU studies were 2.7 and 2.8 IU/dL/IU/kg. Median baseline levels of VWF: CB were 13.0 (r 1.5–101) and 10.4 (r 1.0–84) IU/dL. For the US study, the highest median post-infusion VWF: CB value was 131.5 (r 60–204) IU/dL 15 minutes post-infusion. For the EU study, the highest median VWF: CB value was 147 (r 21–330) IU/dL 30 minutes post-infusion. At 48 hours, levels decreased to near baseline (median: 26.5 [r 10–136] IU/dL in the US study, and 13 [r 2–112] IU/dL in the EU study). Conclusions: VWF: CB values correlated well with VWF: RCo values. Analyses showed that high molecular weight VWF multimers were detectable up to 24 hours post-infusions in all subjects with absent multimers at baseline. The PK data suggest a possibility of slight accumulation of FVIII: C, presumably due to a dynamic stabilization of exogenously injected and endogenously released FVIII. The slow terminal elimination phase of VWF: RCo, compared to shorter distribution phase, suggests a minimal risk of VWF: RCo accumulation, easily managed by adjusting the dosing interval. For surgical coverage, an individual patient’s PK results safely guided initial dosing, with subsequent doses based on their clinical and laboratory responses.

Kinetics of Tissue Distribution and Elimination of Pyrene and 1-Hydroxypyrene Following Intravenous Administration of [14C]Pyrene in Rats

The tissue distribution and elimination of pyrene and 1-hydroxy-pyrene (1-OHP) were evaluated in male Sprague-Dawley rats (210–240 g) following an intravenous injection of 50 μmol/kg of [14C]pyrene. Blood and tissues were removed and urine and feces were collected at 1, 2, 4, 8, 16, and 24 h postdosing. [14C]Pyrene equivalents were measured by liquid scintillation counting, and β-glucuronidase/arylsulfatase-treated blood, tissues, and excreta were analyzed for pyrene and 1-OHP by HPLC/fluorescence. At 1 h, the largest fraction of the dose was found in adipose tissue, essentially as pyrene, and its elimination followed first-order monophasic kinetics with a half-life (t½) of 4.9 h. In blood, liver, kidney, lung, muscle, and gastrointestinal (GI) tract, kinetics of [14C]pyrene equivalents were biphasic and average t½ values for the terminal elimination phase (8 to 24 h) ranged between 6.2 and 8.7 h. Elimination of pyrene in blood and these tissues except the GI tract followed first-order biphasic kinetics with average t½ values of the terminal phase ranging between 3.6 and 5.4 h. In the GI tract, a monophasic elimination kinetics of pyrene was observed with mean t½ value of 3.1 h. Kinetics of 1-OHP in blood and liver showed a monophasic elimination with mean t½ values of 6.7 and 6.2 h, respectively. Kinetics of 1-OHP in the other tissues were biphasic with average t½ values of the terminal elimination phase ranging between 5.2 and 6.2 h. At 24 h, on average, 81.7% of the dose was recovered in the urine (57.2%), feces (18.3%), and GI tract (6.2%) as [14C]pyrene equivalents with 2.7 and 1.9% of dose excreted as total 1-OHP in urine and feces, respectively. At all time points, 1-OHP in urine represented a constant fraction of total 14C in urine and feces. These results indicate that (i) [14C]pyrene was rapidly distributed, metabolized, and eliminated from the body, and (ii) although 1-OHP represents a small percentage of total pyrene eliminated from the body, it remains a reliable indicator of systemic exposure to, and overall elimination of the 14C associated with, this polycyclic aromatic hydrocarbon.