A Re-evaluation and Validation of Ontogeny Functions for Cytochrome P450 1A2 and 3A4 Based on In Vivo Data

Abstract

Dear Editor,We have read with interest the recent study by van Rongen et al. comparing midazolam clearance in obese adolescents with morbidly obese adults [1]. The authors attributed a higher midazolam clearance in the obese adolescents group to higher cytochrome P450 3A enzyme activity when compared to the morbidly obese adults group. However, the surgery type in the obese adults appears to have been exclusively laparoscopic procedures, whereas the surgery in the obese adolescents appears to have been predominantly orthopaedic and otolaryngeal procedures [2,3]. Laparoscopy, with the associated pneumoperitoneum, has been shown to decrease portal venous blood flow by approximately half, with a paradoxical increase in hepatic artery blood flow by approximately 20%, and apparent effects on drug clearance [4]. This effect could also account for the apparent differences in clearance between obese adolescents and morbidly obese adults in the van Rongen et al. study. Depending on the relative timing of the dosing and the onset of the pneumoperitoneum, the effect could also mimic structural pharmacokinetic model elements, such as an extra compartment, as described in Brill et al. [3]. Have the authors considered these effects in the development of the structural model and also the covariate modelling? Some patients in the obese adolescents group underwent bariatric surgery. If these procedures were laparoscopic, then it would be interesting to explore the influence of surgery type on drug clearance. It would also be interesting to model intraperitoneal pressure during laparoscopy, if these data are available, as a covariate effect.Funding No funding was received for the preparation of this letter. Compliance with Ethical Standards Conflict of interest

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

“…After having studied the adult in vitro metabolism in HLM, we assessed whether formation of the primary metabolites O-desmethyltramadol (ODT) and N-desmethyltramadol (NDT) in pediatric HLM is governed by the same enzymes as in adult HLM. The result of this experiment would indicate if our approach of applying known maturation functions (17,35) of the responsible CYP450 enzymes in adults to predict the pediatric clearance is valid. Therefore, in order to assess the fractional activity of ODT and NDT formation relative to adult HLM, pooled adult HLM were incubated with tramadol, as well as probe substrates DEX (CYP2D6) and MDZ (CYP3A4) in pediatric and adult HLM.…”

Using a Vancomycin PBPK Model in Special Populations to Elucidate Case‐Based Clinical PK Observations

“…The nonrenal clearance was estimated by subtracting the renal clearance from the total clearance (CL non‐renal , 1.05 L/hr/70 kg, as shown in Table 1 13–16 ). The estimated nonrenal clearance, which was assumed to be the hepatic clearance, was used to calculate the free hepatic intrinsic clearance (CLu int,H ) with the following equations19: $CL{u}_{\mathrm{int},H}(L/hr)=\frac{Q_{H,B}(L/hr)\times C{L}_{non-renal,B}(L/hr)}{f{u}_B\times (Q_{H,B}(L/hr)-C{L}_{non-renal,B}(L/hr))}$where Q H,B is hepatic blood flow (25.5% of cardiac output20). Cardiac output in adults is provided in the population library as a system parameter.…”

Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

“…Data on midazolam systemic clearance in pediatrics from birth to 17 years were collected from the literature. The literature search strategy and methodology for deconvolution of clearance to arrive at the CL H,B from midazolam systemic clearance (using the blood-to-plasma ratio) and Q H based on cardiac output were explained previously (Salem et al, 2014).…”

“…A drug with 10-fold higher and 10-fold lower CL u . int,H than midazolam was designed by multiplying and dividing the deconvoluted midazolam CL u.int,H by 10 as proposed by Salem et al (2014) to mimic a high-and low-extraction drug, respectively. Then, using the relevant CL u.int,H , Q H , and f u.B in eq.…”