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

Rongen, Anne van; Kervezee, Laura; Brill, Mje; Meir, Hélène van; Hartigh, Jan den; Guchelaar, Henk‐Jan; Meijer, J.H.; Burggraaf, Jacobus; Oosterhout, Floor van

doi:10.1002/psp4.12007

Cited by 24 publications

(22 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is also comparable to the estimated clearance found in a recent study in critically ill children where they also found an effect of inflammation (to compare these values, the results of Vet et al were adapted to values for a 70 kg individual) . In our model, a patient with a healthy albumin level of 45 g l −1 would have a midazolam clearance of 15.3 l h −1 , which is also in line with the results of other studies in healthy volunteers and obese patients , although some studies in obese patients and patients who had undergone bariatric surgery have even higher clearance values . The estimated value for volume of distribution is also similar to that of the studies in critically ill patients and that of the most recent study in obese patients .…”

Section: Discussionsupporting

confidence: 90%

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Franken

Masman

Winter

et al. 2017

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. Because of large inter‐individual variability (IIV), however, the time it takes to achieve adequate sedation varies widely. It would therefore greatly improve clinical care if an individualized dose could be determined beforehand. To find clinically relevant parameters for dose individualization, we performed a pharmacokinetic study on midazolam, 1OH‐midazolam (1‐OH‐M) and 1OH‐midazolam‐glucuronide (1‐OH‐MG) in terminally ill patients. Methods Using nonlinear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 192 samples from 45 terminally ill patients who received midazolam either orally or subcutaneously. The covariates analysed were patient characteristics, co‐medication and blood chemistry levels. Results The data were accurately described by a one compartment model for midazolam, 1‐OH‐M and 1‐OH‐MG. The population mean estimates for midazolam, 1‐OH‐M and 1‐OH‐MG clearance were 8.4 l h−1 (RSE 9%, IIV 49%), 45.4 l h−1 (RSE 12%, IIV 60.5%) and 5.1 l h−1 (RSE 11%, IIV 49.9%), respectively. 1‐OH‐MG clearance was correlated with the estimated glomular filtration rate (eGFR) explaining 28.4% of the IIV in 1‐OH‐MG clearance. In addition, low albumin levels were associated with decreased midazolam clearance, explaining 18.2% of the IIV. Conclusion Our study indicates albumin levels and eGFR as relevant clinical parameters to optimize midazolam dosing in terminally ill patients. The correlation between low albumin levels and decreased midazolam clearance is probably a result of inflammatory response as high CRP levels were correlated in a similar way.

show abstract

Section: Discussionsupporting

confidence: 90%

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Franken

Masman

Winter

et al. 2017

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…26,27 Additionally, CYP3A activity exhibits diurnal variation, with nevirapine clearance rates increasing during the day and reducing at night. 28,29 Differences between morning (AM) and evening (PM) nevirapine trough concentrations ( C min ) have been previously reported 30 and may relate to diurnal variation in the CYP3A -mediated effects on pharmacokinetics.…”

Section: Introductionmentioning

confidence: 89%

“…43 The effect of diurnal variations was investigated using step or cosine functions. 29 Besides weight and age, the other covariates tested were: study site, NRTI treatment backbone, sex, weight-for-age Z-score (WAZ), height-for-age Z-score (HAZ) and formulation. Pharmacogenetic effects were tested as individual SNPs (rs3745274, rs28399499, rs4803419, rs35599367, rs776746, rs3003596, rs2307424, rs2472677, rs2125739) and as metabolizer status determined by SNPs 516G > T and 983T > C [EM, genotype 516GG|983TT; intermediate metabolizer (IM), single variant allele (516GT|983TT or 516GG|983TC); slow metabolizer (SM), two variant alleles (516TT|983CC or 516GT|983TC); ultra-slow metabolizer (USM), 983CC irrespective of 516G > T genotype].…”

Section: Chapas-1mentioning

confidence: 99%

Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

Bienczak

Cook

Wiesner

et al. 2016

J. Antimicrob. Chemother.

View full text Add to dashboard Cite

ObjectivesTo characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children.MethodsNon-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration–time data from 414 children aged 0.3–15 years.ResultsNevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin values in the different metabolizer groups were 5.01 (3.01–7.47), 6.55 (3.65–13.32), 11.59 (5.44–22.71) and 12.32 (12.32–27.25) mg/L, respectively. Evening Cmin values were <3 mg/L in 43% of EM weighing <6 kg and 26% of IM weighing <6 kg, while 73% of SM and 88% of USM in all weight-bands had evening Cmin values >8 mg/L. Cmin was not markedly affected by administration time, but was altered by unequal splitting of the daily dose.ConclusionsDiurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing <6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6–10 kg.

show abstract

“…16 On the other hand, other studies have not found such a pattern. 17,18 In a study conducted in children hospitalized in intensive care units, and with the use of population pharmacokinetics, the light-dark cycle was found to have no impact on CYP3A activity. 19 The primary objective of this prospective study was to test the existence of a circadian rhythm in the hepatic CYP3A activity, and quantify its magnitude.…”

mentioning

confidence: 99%

Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam

Tomalik-Scharte

Suleiman

Frechen

et al. 2014

The Journal of Clinical Pharmacology

View full text Add to dashboard Cite

Diurnal changes in the activity of drug metabolizing enzymes may contribute to the variability in drug disposition and drug effects. The aim of this study was to quantify the circadian rhythmicity exhibited by hepatic CYP3A. A 10 μg/kg intravenous bolus dose, followed by a 30-hour 4 μg/kg/h intravenous infusion of midazolam, used as a probe substrate for hepatic CYP3A activity, was administered to 16 healthy volunteers (8 males and 8 females). Blood samples were drawn hourly for 24 hours after achieving steady state, and plasma concentrations of midazolam and its main metabolite 1-OH midazolam were determined. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. One-compartment pharmacokinetic models best described midazolam and 1-OH midazolam pharmacokinetic disposition. An unequivocal but minor diurnal pattern was identified in the midazolam plasma concentration profiles, which was described using a cosine function with a 24-hours period. The fluctuation in the relative CYP3A activity ranged between 10% above average around 15:00, and 10% below average around 03:00. None of the covariates tested had a significant impact on the parameters estimated. Although a diurnal pattern in hepatic CYP3A activity was identified, its magnitude suggests that it is small and without clinical significance for drug therapy.

show abstract

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

Cited by 24 publications

References 46 publications

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?

Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam

Contact Info

Product

Resources

About