BACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nOptimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both... Show moreBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nOptimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery.\nThe rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4).\nPatients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL (95% CI, 6.7-16).\nThe pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed. Show less
Goetz, M.P.; Sangkuhl, K.; Guchelaar, H.J.; Schwab, M.; Province, M.; Whirl-Carrillo, M.; ... ; Klein, T.E. 2018
RATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies... Show moreRATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, while clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES To prospectively study the relationship between inflammation, organ failure and midazolam clearance, as validated marker of CYP3A mediated drug metabolism, in critically ill children. METHODS From 83 critically ill children (median age 5.1 months (range 0.02-202 months)), midazolam plasma levels (n=532), cytokines (e.g. IL-6, TNF-a), C-reactive protein (CRP) and organ dysfunction scores (PRISM II, PIM2, PELOD), as well as number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MAIN RESULTS In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. Both CRP and organ failure were significantly associated with clearance (p<0.01), explaining both inter-individual and inter-occasional variability. In simulations a CRP of 300 mg/L was associated with a 65% lower clearance compared to 10 mg/L and three failing organs were associated with a 35% lower clearance compared to 1 failing organ. CONCLUSIONS Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity. Show less
