Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations.

Background: In critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner-Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration. Aims and objectives: Phenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner-Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin. Materials and methods: Blood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit. Results: The median [inter-quartile range (IQR)] for Sheiner-Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63-24.53) and 9.82 (6.02-13.85) µg mL-1, respectively. Approximately 53 and 5% of patients were found to be subtherapeutic and supratherapeutic for direct-measured total phenytoin concentrations, respectively. In contrast, on applying the Sheiner-Tozer calculation, 23 and 40% had subtherapeutic and supratherapeutic concentrations, respectively, for total phenytoin concentration. The median (IQR) for direct-measured, routine and Sheiner-Tozer equation calculated free phenytoin concentration were 1.92 (1.06-2.76), 0.98 (0.60-1.39), and 1.71 (1.06-2.45) µg mL-1, respectively. Only 45.7% of patients were in agreement with respect to the therapeutic category when direct-measured free was compared against routine calculation free. Conclusion: In patients with low albumin, free phenytoin concentration based on the Sheiner-Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration. How to cite this article: Wilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022;26(6):682-687.

Systemic exposure to 5-fluorouracil and its metabolite, 5,6-dihydrofluorouracil, and development of a limited sampling strategy for therapeutic drug management of 5-fluorouracil in patients with gastrointestinal malignancy.

AIMS: 5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization. METHODS: This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5-FU. Multiple samples were collected per patient over the slow bolus (15-20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5-FU and DHFU were measured. RESULTS: A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5-FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5-FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5-FU. CONCLUSION: Using body surface area-based dosing with 5-FU, 50-60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44-hour continuous infusion of 5-FU to assist in the therapeutic drug management of patients.

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India.

AIMS: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. METHODS: Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model. RESULTS: Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg-1 , was found to provide adequate drug exposure in most children. CONCLUSIONS: The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin.

Slow parasite clearance, absent K13-propeller gene polymorphisms and adequate artesunate levels among patients with malaria: A pilot study from southern India.

Background: Artemisinin-based combination therapy (ACT) is widely used in India and many generic preparations are available. Delayed response has been reported, suggesting inadequate response to artesunate (AS) or genotypic resistance. We designed a prospective observational study to assess the therapeutic response, elaborate pharmacokinetics of AS and identify Plasmodium falciparum kelch 13 (pfk13) propeller gene polymorphisms among hospitalized Indian patients with severe malaria. Methods: We collected blood samples from adult patients with severe P. falciparum or mixed (P. falciparum and P. vivax) malaria on ACT. We calculated the parasite clearance (CL) half-life using the Worldwide Antimalarial Resistance Network (WWARN) online parasite clearance estimator (PCE). We used the liquid chromatography tandem mass spectrophoto-metry method for simultaneous quantification of AS and dihydroartemisinin. We genotyped longitudinally archived DNA samples obtained pre-treatment (day 0) to study the point mutations in the pfk13 propeller domain. Results: A total of 54 patients with malaria were included, with a majority fulfilling the definitions of severe malaria. The median parasite CL slope half-life was estimated to be 6.44 hours (interquartile range 4.79-10.24). AS pharmacokinetics, assessed in 17 patients, were found to be similar in the groups with rapid (<48 hours) and slow CL (>48 hours) of parasites. No known mutations associated with artemisinin resistance in Southeast Asia were observed in our study participants. Conclusions: Slow parasite CL was seen with a high parasite burden without genotypic evidence of AS resistance. There is a need to standardize definitions of therapeutic efficacy of AS in cases of severe malaria.

Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.

Comparison of the effect of lignocaine instilled through the endotracheal tube and intravenous lignocaine on the extubation response in patients undergoing craniotomy with skull pins: A randomized double blind clinical trial.

BACKGROUND: A desirable combination of smooth extubation and an awake patient after neurosurgical procedures is difficult to achieve in patients with skull pins. Lignocaine instilled into endotracheal tube has been reported to suppress cough by a local mucosal anesthetizing effect. We aimed to evaluate if this effect will last till extubation, if given before pin removal. MATERIALS AND METHODS: A total of 114 patients undergoing elective craniotomy were divided into three groups and were given 1 mg/kg of intravenous (IV), 2% lignocaine (Group 1), placebo (Group 2) and 1 mg/kg of 2% lignocaine sprayed down the endotracheal tube (Group 3) before skull pin removal. The effectiveness of each to blunt extubation response was compared. Plasma levels of lignocaine were measured 10 min after administration of the study drug and at extubation. Sedation scores were noted, immediately after extubation and 10 min later. RESULTS: Two percent of lignocaine instilled through endotracheal route was not superior to the IV route or placebo in attenuating cough or hemodynamic response at extubation when given 20-30 min before extubation. The plasma levels of lignocaine (0.8 µg/ml) were not high enough even at the end of 10 min to have a suppressive effect on cough if given IV or intratracheally (IT). Lignocaine did not delay awakening in these groups. CONCLUSION: IT lignocaine in the dose of 1 mg/kg does not prevent cough at extubation if given 20-30 min before extubation. If the action is by a local mucosal anesthetizing effect, it does not last for 20-30 min to cover the period from pin removal to extubation.

Identification of DPYD variants and estimation of uracil and dihydrouracil in a healthy Indian population.

Aim: This study aimed to identify DPYD variants and the related but previously unexplored phenotype (plasma uracil, dihydrouracil [DHU], and the DHU-to-uracil ratio) in a healthy adult Indian population. Methods: Healthy adult volunteers (n = 100) had their uracil and DHU levels measured and were genotyped for selected variants. Results: Among the nine variants studied, c.1906-14763G>A and c.85T>C were the most prevalent. Participants with any of the variants except for c.85T>C and c.1627A>G had a significantly lower DHU-to-uracil ratio and those with c.1905+1G>A variant had significantly increased uracil concentration compared with wild-type. Conclusion: Participants with five variants were identified as having altered phenotypic measures, and 40% of the intermediate metabolizers had their phenotype in the terminal population percentiles.

Background: 5-fluorouracil (5-FU) is a medicine used in cancer treatment. It is eliminated from body by the enzyme DPD. Identifying deficiency in DPD before initiating 5-FU can save patients from oral, intestinal, and bone marrow toxic effects. Methods: The uracil and dihydrouracil (DHU, produced by DPD enzyme action) levels were measured and DPD gene (for identifying defects) was sequenced in 100 healthy adults. Results: Participants with DPD gene sequence that is known to be defective had higher plasma uracil levels and a low DHU-to-uracil ratio compared with those who did not have a defective gene. Conclusion: Measuring plasma uracil and DHU-to-uracil ratio can help identify people with defective DPD genes.

Model-Informed Rationale for Early Therapeutic Drug Monitoring of Colistin in Critically Ill Patients.

Adequate colistin exposure is important for microbiological clearance. This study was performed in critically ill patients >18 years old to develop a simplified nonparametric pharmacokinetic (PK) model of colistin for routine clinical use and to determine the role of dose optimization. The Non-Parametric Adaptive Grid algorithm within the Pmetrics software package for R was used to develop a PK model from 47 patients, and external validation of the final model was performed in 13 patients. A 1-compartment multiplicative gamma error model with 0-order input and first-order elimination of colistin was developed with creatinine clearance and serum albumin as covariates on elimination rate constant. An R2 for observed vs individual predicted colistin concentrations of 0.92 was obtained in the validation cohort. High interindividual variability in colistin steady-state area under the plasma concentration-time curve (AUC) from from 120 hours to 144 hours (coefficient of variation = 80.1%) and a high interoccasion variability (median coefficient of variation of AUC from time 0 to hours predicted every 8 hours for initial 96 hours after starting colistin = 23.8) was predicted in patients who received this antibiotic for a period of over 152 hours (n = 22). With the model-suggested dose regimen, only 20% of simulated profiles achieved AUC from time 0 to 24 hours in the range of 50 to 60 mg â€¢ h/L due to high variability in population PK. In this group of patients, steady-state colistin concentrations were predicted to be achieved >96 hours after initiation of colistimethate sodium. This study advocates the need for early and repeated therapeutic drug monitoring and dose optimization in critically ill patients to achieve adequate therapeutic concentration of colistin.

Analytical and clinical validation of dried blood spot and volumetric absorptive microsampling for measurement of tacrolimus and creatinine after renal transplantation.

BACKGROUND: Serial monitoring of tacrolimus and serum creatinine after renal transplantation is of vital importance. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the estimation of tacrolimus and creatinine, obtained from dried blood spots (DBS) or by volumetric absorptive microsampling (VAMS) was validated and the two sampling strategies were compared with traditional venous sampling. METHODS: The LC-MS/MS assay was validated using a shared extract for the estimation of tacrolimus and creatinine from DBS and VAMS independently. The relationship between the concentrations in DBS/VAMS specimens and in venous samples was assessed using Passing-Bablok (PB) analysis and the bias between the two methods was determined by the Bland Altman (BA) analysis. RESULTS: The imprecision and bias of tacrolimus and creatinine estimated from DBS and VAMS samples was <12% and was independent of the hematocrit (Hct). Samples were stable for five days at ambient temperature. From the PB regression analysis, correction equations were generated for the prediction of tacrolimus and creatinine values from DBS and VAMS samples. In a separate cohort of patients for validation, the corrected DBS and VAMS concentrations had a mean (95% CI) bias for tacrolimus of -0.64 (-2.98 to 1.70)% and -0.92 (-3.69 to 1.85)% respectively and for creatinine of 1.00 (-2.73 to 4.72)% and -0.71 (-3.74 to 2.32)% respectively. Using DBS and VAMS respectively, for tacrolimus, 91.8 and 89.8% of patient values and for creatinine, 69.4 and 81.6% of patient values were within the limits of clinical acceptance (within 15% agreement against the venous samples). CONCLUSION: We conclude that VAMS is the preferred single sampling option for estimating tacrolimus and creatinine in renal transplant patients.

Continuous infusion versus intermittent bolus doses of fentanyl for analgesia and sedation in neonates: an open-label randomised controlled trial.

OBJECTIVE: Adequate data on fentanyl pharmacokinetics in neonates are lacking. The study was performed to compare serum concentrations and clinical outcome between continuous infusion (CI) and intermittent bolus (IB) doses of fentanyl for analgesia and sedation in neonates. METHODS: In this open-label randomised controlled trial, neonates requiring 24-48 hours of mechanical ventilation and fentanyl administration were recruited. In CI regimen, 1 mcg/kg loading dose was followed by 1 mcg/kg/hour infusion. In IB regimen, 1mcg/kg/dose was administered every 4 hours.Maximum six blood samples were collected in 48 hours from each baby at prespecified time points for estimating serum fentanyl concentration. Secondary outcomes were pain scores (Neonatal Infant Pain Scale and Neonatal Pain, Agitation and Sedation Scale for acute and ongoing pain, respectively) and incidence of adverse effects of fentanyl. RESULTS: 100 neonates were recruited, 53 in CI and 47 in IB group. In CI regimen, median (IQR) serum fentanyl concentration was 0.42 (0.35, 0.46) to 0.61 (0.47, 0.89) ng/mL throughout the infusion period. In IB regimen, median (IQR) peak concentration ranged from 2.21 (1.82, 3.55) to 3.61 (2.91, 4.51) ng/mL and trough concentration 0.41 (0.33, 0.48) to 0.97 (0.56, 1.25) ng/mL for various doses.Median (IQR) peak concentration (Cmax, 3.06 (1.09, 4.50) vs 0.78 (0.49, 1.73) ng/mL; p<0.001) was significantly higher and area under concentration-time curve (AUC0-24, 19.6 (10.4, 33.5) vs 13.2 (10.8, 22.6) µg·hour/L; p=0.12) was higher (though not statistically significant) in IB than CI regimen. Pain scores and adverse effects were comparable between the two regimens. CONCLUSION: CI regimen of fentanyl produces steady serum concentrations, whereas IB regimen produces wide fluctuations in serum concentration with high-peak concentrations. A serum fentanyl concentration of 0.4-0.6 ng/mL produces adequate analgesia and sedation in neonates. TRIAL REGISTRATION NUMBER: CTRI/2014/11/005190.

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India.

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (Cmax), the area under the concentration-time curve from 0-6 h (AUC0-6h) and treatment outcome were determined. Ninety-two percent of patients had an INH Cmax > 3 µg/mL. Seventy-seven percent of patients had a RIF Cmax < 8 µg/mL and 28% of patients had a RIF AUC0-24h < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses.

Cisplatin Concentrations in Long and Short Duration Infusion: Implications for the Optimal Time of Radiation Delivery.

INTRODUCTION: Cisplatin has radiosensitizing properties and the best sensitization to radiotherapy occurs with a higher plasma concentration of cisplatin. To our knowledge the optimal time sequence between chemotherapy and administration of radiation therapy, to obtain maximum effect from concurrent chemoradiation is unclear. AIM: The aim of this study was to measure the two cisplatin infusion regimens in order to determine the total and free cisplatin post infusion concentration changes over time. These changes may have clinical implications on the optimum time of administration of post infusion radiation therapy. MATERIALS AND METHODS: Two cohorts of patients were recruited and both, total and free plasma concentration of cisplatin following long and short durations of intravenous infusion was determined. Blood samples were collected at 0.5, 1, 1.5, 2, 3 and 5 hours from the start of the infusion in the 1hour infusion group and at 2, 3, 3.5, 4, 6 and 24 hours from the start of the infusion, in the 3 hour infusion group. Total and free cisplatin concentrations were measured using a validated HPLC-UV method. RESULTS: The highest concentration of total and free cisplatin was achieved at the end of the infusion in both regimens. Total cisplatin concentration declined 30 minutes after the end of infusion in both the groups. After 1hour of discontinuing cisplatin, the free cisplatin concentration also declined significantly. CONCLUSION: We conclude that radiation should be administered within 30 minutes of completion of the infusion irrespective of the duration of infusion.