Pharmacokinetic interaction of voriconazole and clarithromycin in Pakistani healthy male volunteers: a single dose, randomized, crossover, open-label study.

Background: Voriconazole an antifungal drug, has a potential for drug-drug interactions (DDIs) with administered drugs. Clarithromycin is a Cytochromes P450 CYP (3A4 and 2C19) enzyme inhibitor, and voriconazole is a substrate and inhibitor of these two enzymes. Being a substrate of the same enzyme for metabolism and transport, the chemical nature and pKa of both interacting drugs make these drugs better candidates for potential pharmacokinetic drug-drug interactions (PK-DDIs). This study aimed to evaluate the effect of clarithromycin on the pharmacokinetic profile of voriconazole in healthy volunteers. Methods: A single oral dose, open-label, randomized, crossover study was designed for assessing PK-DDI in healthy volunteers, consisting of 2 weeks washout period. Voriconazole, either alone (2 mg × 200 mg, tablet, P/O) or along with clarithromycin (voriconazole 2 mg × 200 mg, tablet + clarithromycin 500 mg, tablet, P/O), was administered to enrolled volunteers in two sequences. The blood samples (approximately 3 cc) were collected from volunteers for up to 24 h. Plasma concentrations of voriconazole were analyzed by an isocratic, reversed-phase high-performance-liquid chromatography ultraviolet-visible detector (RP HPLC UV-Vis) and a non-compartmental method. Results: In the present study, when voriconazole was administered with clarithromycin versus administered alone, a significant increase in peak plasma concentration (Cmax) of voriconazole by 52% (geometric mean ratio GMR: 1.52; 90% CI 1.04, 1.55; p = 0.000) was observed. Similarly, the area under the curve from time zero to infinity (AUC0-∞) and the area under the concentration-time curve from time zero to time-t (AUC0-t) of voriconazole also significantly increased by 21% (GMR: 1.14; 90% CI 9.09, 10.02; p = 0.013), and 16% (GMR: 1.15; 90% CI 8.08, 10.02; p = 0.007), respectively. In addition, the results also showed a reduction in the apparent volume of distribution (Vd) by 23% (GMR: 0.76; 90% CI 5.00, 6.20; p = 0.051), and apparent clearance (CL) by 13% (GMR: 0.87; 90% CI 41.95, 45.73; p = 0.019) of voriconazole. Conclusion: The alterations in PK parameters of voriconazole after concomitant administration of clarithromycin are of clinical significance. Therefore, adjustments in dosage regimens are warranted. In addition, extreme caution and therapeutic drug monitoring are necessary while co-prescribing both drugs. Clinical Trial Registration: clinicalTrials.gov, Identifier NCT05380245.

Association of Anemia with Parathyroid Hormone Levels and Other Factors in Patients with End-Stage Renal Disease Undergoing Hemodialysis: A Cross-Sectional, Real-World Data Study in Pakistan.

End-stage renal disease (ESRD) patients are mostly managed with maintenance hemodialysis (MHD). ESRD patients on MHD also present with many complications, such as anemia, hyperparathyroidism, and hepatitis prevalence. This study depicts the real-world scenario of anemia among MHD and end-stage renal disease patients in the Pakistani population. A retrospective, multicentric, and real-world data analytical study was conducted at 4 dialysis centers in Pakistan. The study had a sample size of n = 342 patients on maintenance hemodialysis. The data were gathered from the medical records of patients. Data analysis was performed using STATA Version 16. Statistical significance was gauged at a 0.05 level of significance. According to our results, the mean age of the patients was 45 (±15) years. Most of the patients were male (n = 234, 68.4%), whereas 58.1% of the patients were maintained on twice-weekly hemodialysis. The most commonly reported comorbidities were hypertension and diabetes mellitus. The frequency of dialysis (P < 0.01) and comorbidities (P = 0.009) had a significant association with anemia in MHD patients. The majority of the patients had hyperparathyroidism (52%) with anemia. Upon performing binary logistic regression, multivariate analysis displayed a similar odds value for having anemia in patients with every additional month in the duration of hemodialysis (OR 1.01, P = 0.001), the odds of anemic patients having a positive antihepatitis-C antibody (OR 2.22, P = 0.013), and the odds of having anemia in patients in the age category below 45 years (OR 1.93, P = 0.013). In conclusion, the study results depict that every additional month in the duration of hemodialysis, age (<45 years), and positive anti-HCV antibody status, these variables were more likely to have anemia in our study MHD patients. While in our final multivariate model, no statistically significant association was observed between hyperparathyroidism and anemia.

Frequency of De Novo Hepatocellular Carcinoma after Direct-acting Antiviral Therapy for Chronic Hepatitis C: A Prospective Follow-up.

Background: Chronic hepatitis C (CHC) management has changed tremendously after direct-acting antivirals (DAAs) availability. Sustained virological response (SVR) has improved significantly, but one of the major concerns is the chances of de novo hepatocellular carcinoma (HCC) development after DAAs. The objective of the study is to calculate the frequency of newly diagnosed cases of HCC after antiviral therapy for CHC in Pakistan. Materials and methods: This prospective, interventional research was conducted from June 2017 to September 2020. All patients after antiviral therapy for CHC were followed with an ultrasound abdomen and α-fetoprotein, six monthly. Multiphasic computed tomography (CT) of the abdomen was performed in suspected cases. For quantitative variables, the mean and standard deviations were calculated, whereas the qualitative variables were analyzed by frequencies and percentages. Results: Among 180 patients, 110 were men and 70 were women with a mean age of 45.52 ± 11.71 years. One hundred and twenty-six patients were noncirrhotic, 38 had compensated cirrhosis while 16 had decompensated cirrhosis. One hundred and sixty-four (91.11%) patients achieved SVR, of which 22 (12.22%) patients developed new HCC during follow-up. Compensated cirrhosis group had 10 patients, the decompensated group had 12 patients, and the noncirrhotic group had no new HCC cases. Among patients with the new HCC, 12 achieved SVR. Conclusion: The risk of the development of HCC after antiviral treatment is highly significant among patients with liver cirrhosis. So, a strict surveillance strategy should be adopted in every cirrhotic patient following treatment with DAA agents even if they achieve SVR. Clinical significance: Chances of developing HCC are still significantly high even after achieving SVR with DAAs in patients with liver cirrhosis.Patients with liver cirrhosis should be under surveillance for HCC even after achieving SVR after DAAs treatment. How to cite this article: Rasool S, Hanif S, Ahmad A, et al. Frequency of De Novo Hepatocellular Carcinoma after Direct-acting Antiviral Therapy for Chronic Hepatitis C: A Prospective Follow-up. Euroasian J Hepato-Gastroenterol 2022;12(2):73-76.