Anne van Rongen

Impact of obesity on drug metabolism and elimination in adults and children.

The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown.In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes.This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults.Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.

Drug Disposition in Obesity: Toward Evidence-Based Dosing

Obesity and morbid obesity are associated with many physiological changes affecting pharmacokinetics, such as increased blood volume, cardiac output, splanchnic blood flow, and hepatic blood flow. In obesity, drug absorption appears unaltered, although recent evidence suggests that this conclusion may be premature. Volume of distribution may vary largely, but the magnitude and direction of changes seem difficult to predict, with extrapolation on the basis of total body weight being the best approach to date. Changes in clearance may be smaller than in distribution, whereas there is growing evidence that the influence of obesity on clearance can be predicted on the basis of reported changes in the metabolic or elimination pathways involved. For obese children, we propose two methods to distinguish between developmental and obesity-related changes. Future research should focus on the characterization of physiological concepts to predict the optimal dose for each drug in the obese population.

Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents

AIM In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents. METHODS Overweight (BMI for age ≥ 85(th) percentile) and obese (BMI for age ≥ 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post-dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2. RESULTS Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8-55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ). CONCLUSIONS The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.

Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.

BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24–32 weeks’ gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration–time curves (AUC0–500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.

Applied Pharmacometrics in the Obese Population

The pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of drugs in obese individuals may be altered due to associated (patho)physiological changes, necessitating adapted dosing algorithms. Until recently, the obese population was hardly studied in pharmacometric analyses. The influence of obesity on PK and PD parameters has received more attention, given the strong rise in obesity incidence and prevalence across the world. In this review, an overview is given of obesity-related body size descriptors and reported equations quantifying obesity-related changes in population, PK and PD parameters, including how these equations were validated.

Author’s Reply to Reith: “Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults”

We are writing in response to the letter from Drs. Reith and Al-Sallami [1], henceforth referred to as ‘the authors’, commenting on the midazolam paper by van Rongen et al. [2]. In this letter, we explain why it is unlikely that the existence of a pneumoperitoneum would explain the higher midazolam clearance in obese adolescents compared with morbidly obese adults. First, we did not attribute a higher midazolam clearance in the obese adolescents to higher cytochrome P450 (CYP) 3A enzyme activity compared with the morbidly obese adults, but to a lack of suppression of the CYP3A activity in obese adolescents. Furthermore, we stated on multiple occasions in the manuscript (including the first sentence of the Conclusion section of the abstract) that the reported increase in midazolam clearance in obese adolescents with total body weight (TBW) may be explained by increased liver size and/ or increased liver blood flow. Similar to morbidly obese adults, in morbidly obese adolescents increased liver blood flow and liver size may be expected, with heavier individuals having higher liver flows and/or liver size, thereby explaining the increase in clearance with weight in adolescents. The difference with morbidly obese adults in whom no increase with weight was found [3] may, in our opinion, be explained by suppression of CYP3A activity as a result of prolonged inflammation and prolonged obesity. The authors refer to the paper by Liu et al. [4], and state that “laparoscopy, with the associated pneumoperitoneum, has been shown to decrease portal venous blood flow and apparent effects on drug clearance”. In our opinion, this conclusion, which was derived from a study on rocuronium, cannot be directly applied to midazolam. Rocuronium is a high extraction drug and as such its clearance is fully dependent on liver blood flow. Midazolam is an intermediate extraction drug, implying that clearance is dependent on both intrinsic CYP3A activity and blood flow, therefore explanations for our findings should be sought in both areas. Moreover, while rocuronium has a short half-life, clearance of midazolam was determined on the basis of sample collection over 12 h, while pneumoperitoneum is only applied for a maximum duration of 30–45 min. Finally, Liu et al. report on the extended duration of muscle relaxation and not on clearance reduction, therefore it is unknown whether changes in rocuronium clearance are actually the cause of the findings. Finally, Fig. 1 provides information on the type of surgery (adapted from Fig. 5 of the original report [2]). This figure shows that obese adolescents with laparoscopic surgery (green triangles), orthopedic surgery patients (red triangles), and other types of surgery patients (black triangles) are spread randomly around the population clearance (line) according to their weight. If the authors are correct, the bariatric surgery adolescents (green triangles) would show lower (absolute) clearance values than the morbidly obese adults who all underwent laparoscopic bariatric surgery, whereas This author’s reply refers to the letter to the editor at https ://doi. org/10.1007/s4026 2-018-0691-0.

Author’s Reply to Reith: “Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen”

We are writing in response to the letter from Dr David M. Reith, henceforth referred to as ‘the letter’, commenting on a model described in the paper from van Rongen et al. [1, 2]. In short, we disagree with the letter about our conclusions being an artefact, and we argue that our results should be used to inform acetaminophen dosing. Further, we note that our conclusions were supported not only by modeling and simulation, but also by raw data and an independent statistical analysis with area under the plasma concentration–time curve (AUC) values derived by noncompartmental analysis, all of which were covered in the original report. When modeling metabolite pharmacokinetics without measurement of urinary concentrations providing information about the fraction metabolized per pathway, the full system (metabolite formation clearance, volume of distribution of the metabolite, elimination clearance of the metabolite) is not identifiable, as we have elaborated in a previous paper from our group [3]. As a result, some parameters of the metabolite model need to be set to literature values. The letter advocates fixing metabolite volumes of distribution to literature values, which is something we agree with. Therefore, it is unclear why an issue is taken with our published work; we fixed the volumes of distribution of the acetaminophen cysteine ? mercapturate metabolites (fixed to 15.6 L), and the acetaminophen sulphate metabolite (central metabolite volume fixed to 5.66 L) (Table 2 in van Rongen et al. [2]). As the volumes of the acetaminophen cysteine ? mercapturate and sulphate metabolites are fixed to constants, these metabolite volumes of distribution are decreasing relative to body weight. This is consistent with the argument within the letter that ‘‘the volumes of distribution of the metabolites (which are more polar compounds) would be expected to decrease relative to body weight’’. Again, the model we have reported complies with this expectation, and we are confused why the author seems to think there is a problem. The letter states that ‘‘the findings from the plasma concentrations are that plasma concentrations of acetaminophen are decreased in obesity, consistent with a volume of distribution close to total body water’’ and that ‘‘the increased AUC ratios for the metabolites are consistent with a decrease in the volume of distribution of the metabolites, relative to body weight in obese patients’’. We first kindly note that the AUC of a drug compound from t = 0 to t = infinity, be it a parent or a metabolite, is independent of volume of distribution [4]. We do acknowledge that the observed AUC ratios were calculated only from t = 0 to t = 8 h, and not to infinity; however, most of the acetaminophen was eliminated at t = 8 h and therefore it is unlikely that a change in only volume of distribution would cause the decreased acetaminophen exposure in the obese—the clearance of acetaminophen has to be impacted as well. This reply refers to the article available at https://doi.org/10.1007/ s40262-018-0666-1.