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Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Aim: The aim of the study is to determine the factors associated with 28-day mortality in immunocompetent patients with hospital-acquired pneumonia (HAP). Methods: This was a 42-month retrospective cohort study in Chiang Kham Hospital. Patients with HAP diagnosed between January 2013 and June 2016 who did not have an immunocompromised status were recruited into the study. Statistical Analysis Used: Univariable and multivariable binary logistic regression analyses were performed to determine the factors associated with mortality in patients with HAP. Results: A total of 181 HAP patients. The most causative pathogens were nonfermenting Gram-negative bacilli. Fifty-two (28.7%) patients had died within 28 days after HAP diagnosis. Multivariable analysis demonstrated that mechanical ventilation (MV) dependency (adjusted odds ratio [OR] = 3.58, 95% confidence interval [CI] 1.53-8.37, P = 0.003), antibiotic duration (adjusted OR = 0.79, 95% CI 0.70-0.88, P < 0.001), acute kidney injury (adjusted OR = 5.93, 95% CI 1.29-27.22, P = 0.022), and hematologic diseases (adjusted OR = 11.45, 95% CI 1.61-81.50, P = 0.015) were the significant factors associated with 28-day mortality. Conclusions: The factors associated with mortality were MV dependency, HAP duration of treatment, acute kidney injury, and hematologic disease. Early recognition of these factors in immunocompetent patients with HAP and treatment with intensive care may improve the outcome.

Aim: The aim of the study is to determine the factors associated with 28-day mortality in immunocompetent patients with hospital-acquired pneumonia (HAP). Methods: This was a 42-month retrospective cohort study in Chiang Kham Hospital. Patients with HAP diagnosed between January 2013 and June 2016 who did not have an immunocompromised status were recruited into the study. Statistical Analysis Used: Univariable and multivariable binary logistic regression analyses were performed to determine the factors associated with mortality in patients with HAP. Results: A total of 181 HAP patients. The most causative pathogens were nonfermenting Gram-negative bacilli. Fifty-two (28.7%) patients had died within 28 days after HAP diagnosis. Multivariable analysis demonstrated that mechanical ventilation (MV) dependency (adjusted odds ratio [OR] = 3.58, 95% confidence interval [CI] 1.53-8.37, P = 0.003), antibiotic duration (adjusted OR = 0.79, 95% CI 0.70-0.88, P < 0.001), acute kidney injury (adjusted OR = 5.93, 95% CI 1.29-27.22, P = 0.022), and hematologic diseases (adjusted OR = 11.45, 95% CI 1.61-81.50, P = 0.015) were the significant factors associated with 28-day mortality. Conclusions: The factors associated with mortality were MV dependency, HAP duration of treatment, acute kidney injury, and hematologic disease. Early recognition of these factors in immunocompetent patients with HAP and treatment with intensive care may improve the outcome.

In precision medicine, multiple factors are involved in clinical decision-making because of ethnic and racial genetic diversity, family history and other health factors. Although advanced techniques have evolved, there is still an economic obstacle to pharmacogenetic (PGx) implementation in developing countries. The aim of the present study was to provide an alternative pipeline that roughly estimate patient carrier type and prescreen out wild-type samples before sequencing or genotyping to determine genetic status. Fast co-amplification at lower denaturation temperature (COLD)-PCR was used to differentiate genetic variant non-carriers from carriers. The majority of drugs are hepatically cleared by cytochrome P450 (CYP) enzymes and genes encoding CYP enzymes are highly variable. Of all the CYPs, CYP2 family of CYP2C9, CYP2C19, and CYP2D6 isoforms have clinically significant impact on drugs of PGx testing. Therefore, five variants associated with these CYPs were selected for preliminary testing with this novel pipeline. For fast COLD-PCR, the optimal annealing temperature and critical denaturation temperature were determined and evaluated via Sanger sequencing of 27 randomly collected samples. According to precise Tc, to perform in a single-reaction is difficult. However, in this study, this issue was resolved by combination of precise Tc using 10+10+20 cycles. The results showed 100% sensitivity and specificity, with perfect agreement (κ=1.0) compared with Sanger sequencing. The present study provides a prescreening platform by introducing multiplex fast COLD-PCR as a pharmacoeconomic implementation. Our study just present in five variants which are not enough to describe patient metabolic status. Therefore, other actional genetic variants are still needed to cover the actual patient's genotypes. Nevertheless, the proposed method can well-present its efficiency and reliability for serving as a PGx budget platform in the future.

To characterize the pharmacokinetics (PK) of vancomycin in patients in the initial phase of septic shock. Twelve patients with septic shock received an intravenous infusion of vancomycin 30 mg/kg over 2 h. The vancomycin PK study was conducted during the first 12 h of the regimen. Serum vancomycin concentration-time data were analyzed using the standard model-independent analysis and the compartment model. For the noncompartment analysis the mean values ± standard deviation (SD) of the estimated clearance and volume of distribution of vancomycin at steady state were 6.05±1.06 L/h and 78.73±21.78 L, respectively. For the compartmental analysis, the majority of vancomycin concentration-time profiles were best described by a two-compartment PK model. Thus, the two-compartmental first-order elimination model was used for the analysis. The mean ± SD of the total clearance (3.70±1.25 L/h) of vancomycin was higher than that obtained from patients without septic shock. In contrast, the volume of the central compartment (8.34±4.36 L) and volume of peripheral compartment (30.99±7.84 L) did not increase when compared with patients without septic shock. The total clearance of vancomycin was increased in septic shock patients. However, the volume of the central compartment and peripheral compartment did not increase. Consequently, a loading dose of vancomycin should be considered in all patients with septic shock.

Ketoconazole (KTZ) is commonly used by pharmaceutical companies to characterize the worst-case drug interaction for CYP3A substrates under development. Doses of 200 mg and 400 mg of KTZ have been used in human drug interaction studies with midazolam (MDZ). However, large variations in the magnitude of interaction are observed. No single study has compared the inhibitory effect of 200 mg vs. 400 mg of KTZ. Thus, it is unclear whether the worst-case drug interaction study requires 400 mg of KTZ or if a 200 mg dose would suffice. CYP3A5 genotype may in part explain individual variability in metabolism and drug-drug interactions exhibited by CYP3A substrates due to its polymorphic and racially diverse expression. Twenty-four healthy volunteers completed this three-phase, randomized, crossover study. Intravenous (IV) and oral (PO) MDZ were administered on consecutive days alone (control) or on day 6 (IV) and 7 (PO) of KTZ 200 mg or 400 mg daily. Serum samples were assayed for MDZ and KTZ by HPLC-MS. CYP3A5 genotype was determined using allele specific real-time PCR (CYP3A5*3 and *6) and allelic discrimination real-time PCR (CYP3A5*7). The extent of CYP3A inhibition by KTZ was dose dependent with a significantly greater effect following 400 mg KTZ compared to 200 mg KTZ. The baseline systemic and oral clearance values were significantly greater in the group with at least one copy of CYP3A5 functional allele as compared to the group with no functional allele. There was no difference in the extent of interaction after 200 mg or 400 mg KTZ daily between the groups with no and at least one CYP3A5 functional allele. However, the ratios between control and treatment phases of the 1'OH MDZ area under the concentration vs. time curve (AUC) over MDZ AUC among expression groups was significantly different after 200 mg but not after 400 mg KTZ. A model defining KTZ and MDZ pharmacokinetics and employing a stochastic approach for a quantitative drug interaction prediction was developed. The interaction model predicted the extent of interaction reported in published articles. Further research is needed to define the interaction and the variance models.

An innovative probabilistic rule is proposed to predict the clinical significance or clinical insignificance of DDI. This rule is coupled with a hierarchical Bayesian model approach to summarize substrate/inhibitor’s PK models from multiple published resources. This approach incorporates between-subject and between-study variances into DDI prediction. Hence, it can predict both population-average and subject-specific AUCR. The clinically significant DDI, weak DDI, and clinically insignificant inhibitions are decided by the probabilities of predicted AUCR falling into three intervals, (−∞, 1.25), (1.25, 2), and (2, ∞). The main advantage of this probabilistic rule to predict clinical significance of DDI over the deterministic rule is that the probabilistic rule considers the sample variability, and the decision is independent of sampling variation; while deterministic rule based decision will vary from sample to sample. The probabilistic rule proposed in this paper is best suited for the situation when in vivo PK studies and models are available for both the inhibitor and substrate. An early decision on clinically significant or clinically insignificant inhibition can avoid additional DDI studies. Ketoconazole and midazolam are used as an interaction pair to illustrate our idea. AUCR predictions incorporating between-subject variability always have greater variances than population-average AUCR predictions. A clinically insignificant AUCR at population-average level is not necessarily true when considering between-subject variability. Additional simulation studies suggest that predicted AUCRs highly depend on the interaction constant K i and dose combinations.