Population Pharmacokinetic Model Characterizing 24‐Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes

Short- and medium-term impact of bariatric surgery on the activities of CYP2D6, CYP3A4, CYP2C9, and CYP1A2 in morbid obesity

Morbid obesity and bariatric surgery induce anatomical, physiological and metabolic alterations that may alter the body's disposition of drugs. Current literature on this topic is limited and sometimes inconsistent. Cytochrome P450 (CYP) is a superfamily of enzymes that metabolize around 75% of all marketed drugs. The purpose of this study was to evaluate the impact of body mass index and bariatric surgery on CYP activities. Firstly, we evaluated the in vivo activity of 4 major CYP isoenzymes (CYP2D6, CYP3A4, CYP2C9, and CYP1A2) in normal weight, overweight, and morbidly obese individuals. Secondly, we assessed the short- (1 month) and medium-term (6 month) effects of the most commonly employed bariatric surgery techniques (laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) on the activity of these enzymes. CYP3A4 activity was lower in morbidly obese individuals, compared to normal-weight controls. Interestingly, bariatric surgery normalized CYP3A4 activity. In comparison with normal-weight controls, morbidly obese individuals had higher CYP2D6 activity, which was only observed in individuals with two functional alleles for this isoenzyme. Neither body mass index nor surgery had significant effects on CYP2C9 and CYP1A2 activities. Overall, no relevant differences in CYP activities were found between surgical techniques. In conclusion, further studies should evaluate whether the observed alterations in CYP3A4 activity will require dose adjustments for CYP3A4 substrates especially in morbidly obese individuals before and after bariatric surgery.This work was supported by a grant from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias, FISS ETS PI08/90638 co-financed with European Union ERDF funds (European Regional Development Fund). It was also partially supported by grants MTM2015-64465-C2-1-R from the Ministerio de Economía y Competividad (Spain) and 2014 SGR 464 from the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain). JRM acknowledges the EU Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant No. 712949 (TECNIOspring PLUS) from the Agency for Business Competitiveness of the Government of Catalonia. OCN and EPF had grants from ISCIII Juan Rodés JR17/00022 and JR 16/00020

Peri-operative Medication Dosing in Adult Obese Elective Surgical Patients: A Systematic Review of Clinical Studies

Background: Despite the increasing numbers of obese patients undergoing elective surgery, there is a lack of evidence-based dosing guidelines for peri-operative medications in obesity. Objective: The objective was to systematically review the dosing and outcomes of peri-operative medications used in obese elective surgical patients. Methods: Medical subject headings and general keywords were used to systematically search multiple databases (PubMed, EMBASE, Cochrane Library and CINAHL). Studies of medications in obese surgical patients were included if they had a non-obese control or comparative dosing scalar group. The National Health and Medical Research Council GRADE tool was used to assess quality of evidence for each drug. Results: Thirty-three studies of six drug classes were identified: anaesthetics (n = 6), muscle relaxants (n = 10), neuromuscular reversal agents (n = 3), analgesics (n = 2), antibiotics (n = 5) and anticoagulants (n = 7). A variety of dose scalars and/or recommendations was observed for various medications. Lean body weight was proposed as a suitable weight scalar for induction of anaesthesia with propofol whereas total body weight for maintenance of anaesthesia with propofol and depolarizing muscle relaxants. Ideal body weight was reported as an appropriate dosing scalar for non-depolarizing muscle relaxants and neuromuscular reversal agents. Both corrected body weight 40% and ideal body weight were reported as suitable weight scalars for post-operative analgesia with morphine. The standard 2-g dose of cefazolin appeared effective in the prevention of surgical site infection. Body mass index stratified dosing of enoxaparin was effective for venous thromboembolism prevention. Conclusion: No drug recommendation achieved an “Excellent” quality of evidence. Limited data suggest that clinicians should consider each individual class of medication when selecting a dose for obese surgical patients. Routine use of fixed-dosing regimens is likely to under- or overdose obese patients thus predisposing them to adverse drug events or treatment failure leading to patient harm