Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Introduction: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial.

Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English.

Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations.     

A Randomized,Double-Blind,Placebo-Controlled Crossover Study of Cappra? for the Treatment of Mild or Mild to Moderate Erectile Dysfunction in Thai Male

Erectile dysfunction (ED) is one of the major health concerns affects the quality of life among Thai male. The treatment of ED by the first-line drugs is limited to a certain group of patients due to their side effects and costs. Alternative medicine can be beneficial for the treatment of ED. This is a randomized, double-blind, placebo-controlled, crossover study aimed to assess the efficacy and safety of Cappra^®, a traditional herbal medicine which was used in Thailand for decades, for the treatment of mild and mild to moderate ED in Thai patients. A total of 63 patients with mild or mild to moderate ED were randomized to receive Cappra^® or placebo for two weeks in the first period, followed by one week washout period. The patients were switched to the alternative treatment in the second period. The efficacy was assessed by the International Index of Erectile Function (IIEF) questionnaire and adverse events. Sixty one patients completed the study. There was an improvement of IIEF score for all domains in Cappra^® group compared with placebo group. The mean change of IIEF score from baseline for erectile function domain of Cappra^® was significantly higher than placebo (4.87 vs 3.44, p = 0.032). The most common adverse events were dizziness (13.3% Cappra^®, 9.6% placebo), face numbness (1.6% Cappra^®, 0% placebo), and tachycardia (1.6% Cappra^®, 0% placebo). The results from this study demonstrated that Cappra^® is effective and well-tolerated and can be used as alternative therapy for mild and mild to moderate ED.     

Leptospirosis and its pulmonary complications

OBJECTIVE: The aim of this study was to assess the incidence and factors associated with pulmonary complications of leptospirosis. METHODOLOGY: In a retrospective study, patients with a definite diagnosis of leptospirosis following a 6-week period of severe flooding in Hadyai city, Thailand, were reviewed. Pulmonary complications of leptospirosis were defined as the occurrence of respiratory symptoms and an abnormal CXR. The clinical and laboratory test results for patients with and without pulmonary complications were compared. RESULTS: Among the 157 patients with leptospirosis, eight patients had pulmonary complications. Three patients had acute renal failure (ARF) and pulmonary oedema. One patient had ARF and adult respiratory distress syndrome (ARDS). Two patients had ARF, congestive heart failure and pulmonary oedema. One patient had congestive heart failure and pulmonary oedema. One patient had only ARF. Factors associated with pulmonary complications were delayed antibiotic treatment and thrombocytopenia (platelet count < 100 x 10(9)/L). Three patients developed adult respiratory distress syndrome and one died from respiratory failure. CONCLUSIONS: Pulmonary complications and death occur in a low percentage of patients with leptospirosis. Delayed antibiotic treatment and thrombocytopenia are risk factors for the development of pulmonary involvement in leptospirosis.     

Influence of the UGT2B7 -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients

Background and objectives:

A high inter-individual variability in the pharmacokinetics of lamotrigine has been observed. Lamotrigine is primarily metabolized by UGT1A4 and UGT2B7, both of which show genetic polymorphisms. Both genetic and non-genetic factors may influence the pharmacokinetics of lamotrigine. The aim of this study was to determine the pharmacokinetic parameters of lamotrigine and to investigate the effect of genetic variants of UGT1A4 and UGT2B7 and various non-genetic factors on its pharmacokinetics.

Methods:

Four single nucleotide polymorphisms (SNPs; UGT1A4 142 T>G, UGT1A4 70C>T, UGT2B7 372A>G, UGT2B7 -161C>T) were identified using the TaqMan Allelic Discrimination Assay. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check.

Results:

A total of 116 samples were obtained from 75 patients and included in the population analysis. The use of enzyme inducers, valproic acid, and the UGT2B7-161 C>T SNP were found to significantly influence lamotrigine apparent clearance (CL/F). Lamotrigine CL/F in patients carrying the UGT2B7 -161 CT or TT SNP was 18% lower than that in patients carrying the UGT2B7 -161 CC SNP.

Conclusion:

Both genetic and non-genetic factors were found to influence lamotrigine pharmacokinetics. These factors should be considered when determining lamotrigine dosing. The model presented here could be useful for lamotrigine dose adjustment in clinical practice.     

Population pharmacokinetics of lamotrigine in elderly patients

Lamotrigine is being used more frequently in elderly patients. Dosing of lamotrigine in elderly patients is based largely on studies from younger adults and not evidence-based data from elderly patients. The goal of this study is to determine the pharmacokinetic parameters, such as clearance, and the factors that have a significant effect on these parameters to provide evidence-based information that can be used to dose elderly patients taking lamotrigine. Lamotrigine plasma concentrations from 148 elderly patients (aged 59-92 years) were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check. The results showed that the blood urea nitrogen/serum creatinine ratio, weight, and phenytoin use significantly affect apparent clearance of lamotrigine. These results show that clinicians may need to take into account these covariates when dosing lamotrigine in this population.     

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01138241","term_id":"NCT01138241"}}NCT01138241.)