Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients.

The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were higher in SP than in BP (median AUC0-24, 7.01 versus 2.97 mg · liter-1 · h, respectively). The median (range) SP-to-BP AUC0-24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC0-24 or TFV SP-to-BP AUC0-24 ratio on spVL was not significant (P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

Diagnostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: a systematic review and meta-analysis.

AIMS: This systematic review aimed to investigate the diagnostic accuracy of combined cardiac troponin (cTn) and copeptin assessment in comparison to cTn alone for early rule-out of acute myocardial infarction (AMI). METHODS: Primary studies were eligible if they evaluated diagnostic accuracy for cTn with and without copeptin in patients with symptoms suggestive of AMI. AMI was defined according to the universal definition, using detection of cTn as a marker for myocardial necrosis. Eligible studies were identified by searching electronic databases (Medline, EMBASE, Science Citation Index Expanded, CINAHL, Pascal, and Cochrane) from inception to March 2013, reviewing conference proceedings and contacting field experts and the copeptin manufacturer. RESULTS: In 15 studies totalling 8740 patients (prevalence of AMI 16%), adding copeptin improved the sensitivity of cTn assays (from 0.87 to 0.96, p=0.003) at the expense of lower specificity (from 0.84 to 0.56, p<0.001). In 12 studies providing data for 6988 patients without ST-segment elevation, the summary sensitivity and specificity estimates were 0.95 (95% CI 0.89 to 0.98) and 0.57 (95% CI 0.49 to 0.65) for the combined assessment of cTn and copeptin. When a high-sensitivity cTnT assay was used in combination with copeptin, the summary sensitivity and specificity estimates were 0.98 (95% CI 0.96 to 1.00) and 0.50 (95% CI 0.42 to 0.58). CONCLUSION: Despite substantial between-study heterogeneity, this meta-analysis demonstrates that copeptin significantly improves baseline cTn sensitivity. Management studies are needed to establish the effectiveness and safety of measuring copeptin in combination with high-sensitivity cTnT for early rule-out of AMI without serial testing.

Analytical evaluation of a high-sensitivity troponin T assay and its clinical assessment in acute coronary syndrome.

BACKGROUND: The recently developed, highly sensitive cardiac troponin T (hs-cTnT) immunoassay improves the detection of acute myocardial infarction (AMI). However, this assay requires further analytical and clinical evaluation. METHODS: Imprecision, linearity, limits of quantification and interferences were evaluated; hs-cTnT was compared with a conventional cardiac troponin I assay (cTnI), performed on an X-pand(®)HM, in a population of patients with suspected AMI. Finally, the 99th percentile cut-off point for a reference population was explored in 213 healthy control subjects. RESULTS: Imprecision analysis demonstrated coefficients of variation (CVs) below 4%, linearity showed a 0.999 coefficient of correlation, with excellent recovery (99.9%) and a limit of quantification (10%CV) was found at 9.2 ng/L. A negative interference (>20%) with haemolysis was observed when supplemental haemoglobin was above 0.25 g/dL. Patients with suspected AMI more frequently displayed an increased hs-cTnT (83%) than an increased cTnI (55%, P < 0.01). Unstable angina was present in 63% of patients with an increased hs-cTnT associated with no increase in cTnI. The 99th percentile value for our reference population was 16.9 ng/L. In 213 healthy blood donors, hs-cTnT levels were significantly correlated with age (P < 0.0001), and were higher in men than in women (P < 0.0001). CONCLUSIONS: The analytical performance of hs-cTnT complied with the international guidelines for AMI detection. Determining the degree of haemolysis in a sample is of paramount importance to the interpretation of hs-cTnT results. The 99th percentile value of our reference population was established.