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This article summarizes the lessons learned from the COCKTAIL study: an open, three‐armed, single‐center study including patients with obesity scheduled for treatment with Roux‐en‐Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal‐ to overweight control group. The clinical implications of the results from multiple peer‐reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug‐metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion‐transporting polypeptide (OATP) 1B1 and P‐glycoprotein (P‐gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity‐related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow‐up due to high inter‐ and intraindividual variability in these patients, particularly following RYGB. [ABSTRACT FROM AUTHOR]

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross‐sectional analysis; 29 with T2DM and obesity (T2DM‐obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM‐obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform‐specific. [ABSTRACT FROM AUTHOR]

Aim: Roux‐en‐Y gastric bypass (RYGB) may influence drug disposition due to surgery‐induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short‐ and long‐term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5‐hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross‐sectionally compare these CYP‐activities with normal‐to‐overweight controls. Methods: This trial included patients with severe obesity preparing for RYGB (n = 40) or diet‐induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3‐week low‐energy diet (<1200 kcal/day, weeks 0‐3) followed by a 6‐week very‐low‐energy diet or RYGB (both <800 kcal/day, weeks 3‐9). Follow‐up time was 2 years, with four pharmacokinetic investigations. Results: Mean ± SD weight loss from baseline was similar in the RYGB‐group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB −30 ± 6.9%, diet −3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3‐9), but not in the diet‐group (between‐group difference −0.30 [−0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7‐fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion: Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed. [ABSTRACT FROM AUTHOR]

Mathematical models, such as physiologically‐based pharmacokinetic models, are used to predict, for example, drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these interindividual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug‐metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (CYP) (e.g., CYP2U1) and the amine oxidase (flavin‐containing) (e.g., monoamine oxidase A (MAOA)) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor‐matched tissues. These proteins also do not correlate with physiological factors such as body mass index, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, interindividual differences were considerable, with implications for personalized prediction models and systems pharmacology. [ABSTRACT FROM AUTHOR]

It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet‐induced (n = 41) weight‐loss, and controls (n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (<1200 kcal/day) followed by a 6‐week very‐low‐energy‐diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight‐loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between‐group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A‐activity is not only dependent on weight‐loss through RYGB. [ABSTRACT FROM AUTHOR]

Rosuvastatin is a frequently used probe to study transporter‐mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time‐concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293‐transfected cells, and developed a semimechanistic model with a bottom‐up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measured in vivo plasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two‐fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (Cmax; 76%; AFE: 1.05), and terminal half‐life (t1/2; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC‐guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice‐daily tacrolimus in a real‐life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting‐state and under real‐life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting‐conditions: 45% higher peak‐concentration and 20% higher AUC following the morning dose. In the real‐life nonfasting setting, the PK‐profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting‐state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real‐life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting‐state, whereas flatter PK‐profiles and no circadian variation was present in a real‐life, nonfasting setting. [ABSTRACT FROM AUTHOR]

Drug dosing is challenging in patients with end‐stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P‐glycoprotein (P‐gp)/organic anion‐transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (−3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P‐gp/OATP activity. [ABSTRACT FROM AUTHOR]

Summary: Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before‐after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux‐en‐Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long‐term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss. [ABSTRACT FROM AUTHOR]

Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus-treated transplant recipients? Keywords: adverse drug reactions; drug metabolism; other; pharmacokinetics; transplantation EN adverse drug reactions drug metabolism other pharmacokinetics transplantation 2535 2535 1 11/28/20 20201201 NES 201201 The article by Campagne et al1 highlights a timely issue in modern immunosuppressive therapy of transplanted patients; what is the impact of tacrolimus (Tac) exposure on extrarenal adverse effects? Adverse drug reactions, drug metabolism, other, pharmacokinetics, transplantation. [Extracted from the article]

We appreciate the input of Drs Yildiz and Yildiz.[1] They suggest an addition to our review on the bioavailability of immunosuppressive drugs after bariatric surgery,[2] specifically in relation to transplantation surgery. Our general recommendation would therefore be to use standard TDM procedure in patients transplanted after bariatric surgery and to intensify TDM in case of bariatric surgery in transplanted patients. [Extracted from the article]