ABSTRACT
The role of therapeutic drug monitoring in pediatric antiretroviral therapy is unclear. A little pharmacokinetic datum from clinical practice exists beyond controlled approval studies including clinically stable children. The aim of this study is to quantify LPV exposure of critically ill infants in an ICU and-by identifying risk factors for inadequate exposure-to define sensible indications for TDM in pediatric HIV care; in addition, assume total drug adherence in ICU to compare LPV exposure with a setting of unknown adherence. In this prospective investigation, 15 blood samples from critically ill infants in the pediatric ICU at Tygerberg Hospital were analyzed for LPV-serum concentrations. They were then compared to those of 22 blood samples from out-patient children. Serum-level measurements were performed with an established high-performance liquid chromatography method. All LPV-serum levels of ICU patients were higher than a recommended Ctrough (= 1.000 ng/ml), 60% of levels were higher than Cmax (8.200 ng/ml). Partly, serum levels reached were extremely high (Maximum: 28.778 ng/ml). Low bodyweight and age correlated significantly with high LPV concentrations and were risk factors for serum levels higher than Cmax. Significantly fewer serum levels from infants in ICU care (mean: 11.552 ng/ml ± SD 7760 ng/ml) than from out-patient children (mean: 6.756 ng/ml ± SD 6.003 ng/ml) were subtherapeutic (0 vs. 28%, p = 0.008). Under total adherence in the ICU group, there were no subtherapeutic serum levels, while, in out-patient, children with unknown adherence 28% of serum levels were found subtherapeutic. Low bodyweight and age are risk factors for reaching potentially toxic LPV levels in this extremely fragile population. TDM can be a reasonable tool to secure sufficient and safe drug exposure in pediatric cART.
Subject(s)
Critical Illness , HIV Protease Inhibitors/pharmacokinetics , Lopinavir/pharmacokinetics , Serum/chemistry , Chromatography, High Pressure Liquid , Female , HIV Protease Inhibitors/administration & dosage , Humans , Infant , Intensive Care Units, Neonatal , Lopinavir/administration & dosage , Male , Prospective Studies , South AfricaABSTRACT
BACKGROUND: In antiretroviral treatment the role of therapeutic drug monitoring via measurement of serum levels remains unclear, especially in children. AIM: To quantify exposure to LPV and EFV in children receiving therapy in a routine clinical setting in order to identify risk factors associated with inadequate drug exposure. METHOD: A prospective study was conducted in a routine clinical setting in Tygerberg Children's Hospital, South Africa. A total of 53 random serum levels were analyzed. Serum concentrations were determined by an established high-performance liquid chromatography method. RESULTS: Of 53 HIV-infected children treated with lopinavir (nâ=â29, median age 1·83 y) or efavirenz (nâ=â24, median age 9·3 years), 12 showed serum levels outside the therapeutic range (efavirenz) or below Cmin (lopinavir). Low bodyweight, rifampicin co-treatment, and significant comorbidity were potential risk factors for inadequate drug exposure. CONCLUSION: These findings, together with previous studies, indicate that therapeutic drug monitoring can improve the management of antiretroviral therapy in children at risk.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Benzoxazines/pharmacokinetics , Drug Monitoring , HIV Infections/drug therapy , Lopinavir/pharmacokinetics , Serum/chemistry , Adolescent , Alkynes , Anti-HIV Agents/administration & dosage , Benzoxazines/administration & dosage , Child , Child, Preschool , Chromatography, Liquid , Cyclopropanes , Female , Hospitals , Humans , Infant , Lopinavir/administration & dosage , Male , Prospective Studies , South AfricaABSTRACT
OBJECTIVES: Posaconazole is broadly used for antifungal prophylaxis and therapy. Current data suggest a concentration-dependent effect. Unlike other triazoles, cytochrome P450 is not a relevant route of biotransformation for posaconazole but glucuronidation, which might lead to a different spectrum of drug interactions. For benzodiazepines, the major metabolic pathway involves oxidation, but some, including lorazepam and temazepam, undergo conjugation to glucuronic acid. RESEARCH DESIGN AND METHODS: Since 2006 serum levels of posaconazole are determined regularly in all hospitalized patients with intake of this triazole. Here we investigate posaconazole concentration at steady state in relation to the concomitant medication of benzodiazepines. RESULTS: While similar posaconazole concentrations were determined in samples obtained from patients receiving temazepam when compared to samples without any benzodiazepine, a relevant reduction of posaconazole concentration could be observed in patients with concomitant intake of lorazepam. This difference in posaconazole concentration with or without concomittant intake of lorazepam, was consistently significant for analyses of all samples (median 336 ng/ml vs. 585 ng/ml, p 0.001), for the average concentrations (569 ng/ml vs. 276 ng/ml, p 0.039), and for patients receiving a total daily dose of 800 mg posaconazole (292 ng/ml vs. 537 ng/ml, p 0.003). There was also a similar, but not significant trend for patients with a prophylactic dosage of 200 mg posaconazole three times daily (689 ng/ml vs. 512 ng/ml, p 0.186). CONCLUSIONS: In this retrospective study, analyzing blood samples from daily clinical practice of patients in various clinical settings and with different indications for antifungal therapy, concomitant medication of lorazepam was associated with decreased posaconazole concentrations. Therefore, lorazepam but not temazepam might induce posaconazole clearance by glucuronidation.
Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Antifungal Agents/pharmacokinetics , Benzodiazepines/pharmacokinetics , Lorazepam/pharmacokinetics , Temazepam/pharmacokinetics , Triazoles/pharmacokinetics , Anti-Anxiety Agents/administration & dosage , Antifungal Agents/administration & dosage , Benzodiazepines/administration & dosage , Dose-Response Relationship, Drug , Drug Interactions , Humans , Lorazepam/administration & dosage , Male , Retrospective Studies , Serum/metabolism , Temazepam/administration & dosage , Triazoles/administration & dosageABSTRACT
For posaconazole, drug monitoring is suggested, but the relevance of timing for the determination of posaconazole concentration (PC) remains unclear. We investigated the variation of PC before and 4 and 8 h after the administration of 400 mg of posaconazole. Mean concentrations were 645, 678, and 616 ng/ml. The differences between trough and maximum concentrations were below 20% in 17 and below 30% in 20 of 25 patients. Hence, untimed posaconazole plasma concentrations give reliable information for most patients.
Subject(s)
Antifungal Agents/blood , Antifungal Agents/pharmacokinetics , Triazoles/blood , Adult , Aged , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Female , Humans , Male , Middle Aged , Triazoles/administration & dosage , Triazoles/pharmacokinetics , Triazoles/therapeutic use , Young AdultABSTRACT
PURPOSE: Sorafenib is recommended for therapy of advanced hepatocellular carcinoma and renal cell carcinoma. Preclinical data indicate a relation between dose and antitumor efficacy. In clinical trials, adverse events improve after dose reduction suggesting a dose-dependent toxicity. Given dose has a direct impact on the drug serum concentration, but the latter also can be influenced by multiple factors, including interaction and metabolisation. To enable the investigation of concentration-related effects, an easy and sensitive assay for sorafenib drug monitoring is essential. METHODS: A high-performance liquid chromatography (HPLC) analysis involving an extraction with diethyl ether followed by separation on a Pinnacle™ DB C18 column and quantitation by UV absorbance at 260 nm was established. Sorafenib concentrations in samples of serum and peritoneal fluid have been determined. RESULTS: The assay was validated for serum samples and is linear over the concentration range of 100-5,000 ng/ml with a determination coefficient of >0.999. The limit of detection is 0.25 ng/ml. The intra- and inter-day coefficients of variation were below 3.03%. Sorafenib recovery in spiked probes of peritoneal fluid was above 85%. Sorafenib concentrations in 44 serum samples and 14 probes of peritoneal fluid have been determined with a mean of 3,328 and 1,380 ng/ml, respectively (standard deviation 2,267 and 659 ng/ml). CONCLUSIONS: A sensitive and selective HPLC method for the determination of sorafenib in human serum was developed and also verified for peritoneal fluid. This method provides a useful tool for pharmacokinetic investigations as well as for therapeutic drug monitoring of sorafenib.
Subject(s)
Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Ascitic Fluid/chemistry , Benzenesulfonates/blood , Benzenesulfonates/pharmacokinetics , Drug Monitoring , Pyridines/blood , Pyridines/pharmacokinetics , Antineoplastic Agents/adverse effects , Benzenesulfonates/adverse effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Renal Cell/drug therapy , Chromatography, High Pressure Liquid , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/adverse effects , Sensitivity and Specificity , SorafenibABSTRACT
A simple, sensitive, and selective high-performance liquid chromatographic method for the simultaneous determination of voriconazole and posaconazole concentrations in human plasma was developed and validated. Quantitative recovery following liquid-liquid extraction with diethyl ether was achieved. Linearity ranged from 0.10 to 20.0 microg/ml for voriconazole and from 0.05 to 10.0 microg/ml for posaconazole. The intra- and interday coefficients of variation were less than 8.5%, and the lower limits of quantitation were <0.05 microg/ml.
Subject(s)
Antifungal Agents/blood , Chromatography, High Pressure Liquid/methods , Pyrimidines/blood , Triazoles/blood , Humans , Reproducibility of Results , VoriconazoleABSTRACT
In order to evaluate recent alcohol consumption, a very sensitive and specific gas chromatographic method for ethanol determination in human urine samples was developed. The non-invasive method was performed without any pretreatment and carried out on a Stabilwax capillary column, 30 m x 0.53 mm x 1.0 microm film thickness. Helium was used as carrier gas with a constant inlet pressure of 27.72 kPa (0.277 bar) and a flame ionization detector (FID). Quantification was performed with the use of acetonitrile as an internal standard (IS). The calibration curve was linear throughout the concentration range from 0.5 to 500 mg/l. The calculated intra- and inter-day coefficients of variation were below 8%. A clear chromatographic separation of ethanol from methanol, acetone, 1-propanol and 2-propanol was achieved.