Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

BACKGROUND AND OBJECTIVE: Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. METHODS: Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132 µM, while 990 µM was considered as the threshold for toxic concentration. RESULTS: Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range. CONCLUSION: A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

Evaluation of the Association between Single Nucleotide Polymorphisms of Metabolizing Enzymes with the Serum Concentration of Paracetamol and Its Metabolites.

Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the CYP enzymes result in modified enzymatic activity. The present study was carried out to evaluate the prevalence of SNPs related to paracetamol metabolism and principal metabolites in critically ill patients, and those with chronic kidney disease. The present study is a cross-sectional study carried out in adults (>21 years) requiring intravenous paracetamol as part of their standard of care. Details regarding their demographics, and renal and liver function tests were collected. Blood was withdrawn for the analysis of paracetamol and their metabolites, and the SNPs of key CYP enzymes. Paracetamol/paracetamol glucuronide (P/PG), paracetamol/paracetamol sulphate (P/PS) and PG/PS were estimated. Acute liver injury (ALI) and renal dysfunction were defined using standard definitions. We observed a significant prevalence of SNPs in CYP1A2*1C, CYP3A4*3, CYP1A2*1K, CYP1A2*6, CYP2D6*10, and CYP2E1*2 amongst the 150 study participants. Those with CYP1A2*6 (CC genotype) were observed with significantly lower PG and PS concentrations, and a higher P/PS ratio; CYP2D6*10 (1/1 genotype) with a significantly lower PG concentration and a higher P/PG ratio; and CYP1A2*1K (CC genotype) was observed with a significantly higher PG/PS ratio. Good predictive accuracies were observed for determining the SNPs with the cut-off concentration of 0.29 µM for PS in determining CYP1A2*1K, 0.39 µM for PG and 0.32 µM for PS in determining CYP1A2*6 genotype, and 0.29 µM for PG in determining the CYP2D6*10 genotype. Patients with renal dysfunction were observed with significantly greater concentrations of paracetamol, PG and P/PS, and PG/PS ratios, with a lower concentration of PS. No significant differences were observed in any of the metabolites or metabolite ratios in patients with ALI. We have elucidated the prevalence of key CYP enzymes involved in acetaminophen metabolism in our population. Alterations in the metabolite concentrations and metabolic ratios were observed with SNPs, and in patients with renal dysfunction. Population toxicokinetic studies elucidating the dose-response relationship are essential to understand the optimized dose in this sub-population.

Does fasting during Ramadan influence the therapeutic effect of warfarin?

WHAT IS KNOWN AND OBJECTIVES: The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. METHODS: Patients receiving warfarin for at least 1 year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1 month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. RESULTS AND DISCUSSION: One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3 months (pre-Ramadan, Ramadan and post-Ramadan periods). WHAT IS NEW AND CONCLUSION: Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.

Evaluation of inter-patient variability in the pharmacodynamic indices of warfarin.

OBJECTIVES: Warfarin exhibits huge inter-individual variability in therapeutic response. We assessed the extent and the factors affecting inter-individual variability in the anticoagulation control using pre-validated pharmacodynamic indices. METHODS: Patients receiving warfarin for at least 6 months were recruited. CHA2DS2-VASc, HASBLED, SAMe-TT2R2 scores, warfarin sensitive index (WSI), log-INR variability, and warfarin composite measure (WCM) were assessed. National Institute for Health and Care Excellence (NICE) guideline was adhered for assessing the anticoagulation control using time in therapeutic range (TTR) (TTR < 65%-poor; and TTR ≥ 65%-good). Odds ratio [95% confidence interval] was the effect estimate measure. RESULTS: Eighty-seven (39.5%) of the patients were poorly anticoagulated. Those with lower HASBLED [OR: 0.3; 0.1, 0.6] and SAMe-TT2R2 scores [OR: 0.2; 0.04, 0.7] and higher CHA2DS2-VASc score [OR: 1.8; 1.1, 1.3] predicted good anticoagulation control. Thirty-five (15.9%) patients had high INR variability. Lower TTR, shorter duration of therapy, and higher WSI were observed in patients with high INR variability, and presence of drugs with potential interaction significantly predicted high INR variability. CONCLUSION: Significant numbers of our patients on warfarin had poor anticoagulation control and high INR variability. We have identified duration of therapy, CHA2DS2-VASc score, and WSI as reliable predictors for anticoagulation control and INR variability.

Dose Optimization of Gentamicin in Critically Ill Neonates.

BACKGROUND: Appropriate dosing of gentamicin in critically ill neonates is still debated. OBJECTIVE: To assess the peak concentration (Cmax) and area-under-the-time-concentration curve (AUC0-24) of gentamicin and to simulate the recommended doses using the Monte Carlo method. METHODS: This was a retrospective study on critically ill neonates carried over a one-year period. The demographic characteristics, dosage regimen and gentamicin concentrations were recorded for each neonate. Using Bayesian pharmacokinetic modeling, Cmax and AUC0-24 were predicted. Dose recommendations for the target Cmax (µg/ml) of 12 were obtained, and Monte Carlo simulation (100,000 iterations) was used for predicting the pharmacokinetic parameters and recommended doses for various birth weight categories. RESULTS: Eighty-two critically ill neonates (with an average gestational age of 33.7 weeks; and birth weight of 2.1 kg) were recruited. Higher Cmax and AUC0-24 values were predicted in premature neonates, with greater cumulative AUCs in extremely preterm neonates. The average administered dose was 4 mg/kg/day and 75% of the participants had Cmax greater than 12 µg/ml following a single dose, and 85% were found to be at steady state. On the contrary, only 25% of the study population had the recommended AUC0-24 (above 125 µg-hr/ml). Simulation tests indicate that 90% of the critically ill neonates would achieve recommended Cmax with doses ranging between 5 and 6 mg/kg/day. CONCLUSION: Currently used dose of 4 mg/kg/day is adequate to maintain Cmax in a large majority of the study population, with one-fourth population reporting the recommended AUC0-24. Increasing the dose to 5-6 mg/kg/day will more likely help to achieve both the recommended Cmax and AUC0-24 values.

Health-related quality of life in patients receiving oral anti-coagulants: a cross-sectional study.

OBJECTIVES: Patients receiving long-term anticoagulants were reported with varied health-related quality of life (HrQoL). We assessed HrQoL in patients receiving either warfarin or dabigatran from a tertiary care hospital. METHODS: A cross-sectional study was carried out following consent from patients on oral anticoagulants. Demographics, prothrombin time international normalized ratio (PT-INR), and drug-related details were collected. A validated Arabic version of the perception of anticoagulant treatment questionnaire (PACT-2) was used to assess HrQoL under three dimensions: convenience; burden of disease; and treatment satisfaction. RESULTS: One-hundred and fifty patients were recruited. Overall good quality of life was observed as indicated by the average score of 80.3 in the warfarin group and, moderate in the dabigatran (average score of 68). Highly adherent and elderly patients receiving warfarin were significantly more likely to have good quality of life. Therapeutic PT-INR and high medication adherence were the primary domains significantly associated with good quality of life amongst patients with warfarin. CONCLUSION: We observed good quality of life in patients receiving warfarin particularly those in the categories of elderly, with therapeutic PT-INR and high medication adherence. Small sample size with dabigatran precludes any firm conclusions.