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



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.



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.



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.
Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, Netherlands.
Linda G
0000-0001-6436-9825
LG
Franken
Palliative Care Centre, Laurens Cadenza, Rotterdam, Netherlands.|Intensive Care, Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.
Anniek D
AD
Masman
Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, Netherlands.
Brenda C M
BCM
de Winter
Palliative Care Centre, Laurens Cadenza, Rotterdam, Netherlands.
Frans P M
FPM
Baar
Intensive Care, Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.|Pain Expertise Centre, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.
Dick
D
Tibboel
Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, Netherlands.
Teun
T
van Gelder
Department of Hospital Pharmacy, Erasmus Medical Centre, Rotterdam, Netherlands.
Birgit C P
BCP
Koch
Hospital Pharmacy - Clinical Pharmacology, Academic Medical Centre, Amsterdam, Netherlands.
Ron A A
RAA
Mathot
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D034141:Hypoalbuminemia / Q000097:blood*; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D017711:Nonlinear Dynamics; D010166:Palliative Care / Q000379:methods; D057285:Precision Medicine / Q000379:methods; D065667:Renal Elimination; D019452:Terminally Ill; D013997:Time Factors
D006993:Hypnotics and Sedatives; C061795:1-hydroxymethylmidazolam glucuronide; C040081:1-hydroxymethylmidazolam; D008874:Midazolam
NONMEM; drug metabolism; palliative care; pharmacokinetics; sedation