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.

Die Therapie mit pegyliertem Interferon alfa (IFN) und Ribavirin (RBV) stellt den aktuellen Therapiestandard in der Behandlung der chronischen Hepatitis C dar. Der Ribavirin-Exposition kommt im Hinblick auf einen Therapieerfolg eine große Bedeutung zu. Über die Pharmakokinetik von RBV im praktischen Therapieverlauf ist bislang wenig bekannt.

ABSTRACT 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 μg/ml for voriconazole and from 0.05 to 10.0 μg/ml for posaconazole. The intra- and interday coefficients of variation were less than 8.5%, and the lower limits of quantitation were <0.05 μg/ml.

Tipranavir (TPV) is a selective nonpeptidic HIV-1 protease inhibitor (PI) which is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily in combination with low-dose ritonavir. The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial hemorrhage have been associated with the drug. Tipranavir also has a complex drug interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.

The protease inhibitor Lopinavir (LPV) combined with low dose ritonavir (r) in the formulation of a soft gelatine capsule (SGC) has been widely used in antiretroviral therapy and has been shown to produce safe therapeutic plasma levels. In June 2006, the LPV/r combination was approved as a tablet (TBL) in Germany and since then has replaced the capsule form. The purpose of this study was to analyze and compare pharmacokinetics of Lopinavir both in the new meltrex tablet formulation and the LPV/r soft gelatine capsule during long-term treatment of HIV.Methods: Included in this study were all patients followed at multiple study centers between January 2003 and August 2007 for whom LPV plasma levels were archived during therapeutic drug monitoring. A total of 4010 LPV plasma levels from 721 patients met these inclusion criteria. From these, those patients for whom complete data sets were missing were excluded from the study. Complete data sets were defined as those data that included information regarding cumulative daily dose, the patient's anti-retroviral drug regimen, and the time of measurement after drug intake. A total of 571 LPV plasma levels from 138 patients met the full criteria for inclusion in this retrospective study. Additionally, a small prospective study of LPV plasma levels in 6 patients with 24 data points was conducted in order to increase the reliability of this report.Results: At 3 h after dosing, plasma levels of LPV were significantly higher in patients who had received the meltrex tablet (Mdn = 10030 ng/ml, min = 3323, max = 17280) compared to those who had received the soft gelatine capsule (Mdn = 7964 ng/ml, min = 120, max = 17900). This difference was statistically significant (p < 0.05). There were no statistically significant differences between the LPV plasma levels of the tablet and the capsule at 6, 9 and 12 h after dosing. Additionally, there were no differences between the trough levels of LPV in the two formulations. However, great variances of plasma levels were detected at time 12 h after dosing for both treatment groups (s(capsule) = 3213 ng/ml, s(tablet) = 2273 ng/ml).Conclusion: The LPV/r tablet formulation is able to produce equivalent to significantly higher plasma levels of LPV when compared with the SGC formulation at time 3 h after drug intake. In addition, the known sex difference in the pharmacokinetic profile of the tablet formulation was verified in this study.

Einleitung: In der Therapie der chronischen Hepatitis C kommt der Ribavirin (RBV)-Exposition bereits in den ersten Behandlungswochen eine große Bedeutung im Hinblick auf ein Therapieansprechen zu. Über die sich im Verlauf der Therapie einstellenden RBV-Plasmakonzentrationen (RBV-C) ist bislang wenig bekannt.

Chronic liver disease is often found in HIV infected patients. LPV as first choice drug is often used over long time periods. TDM as a tool in patients care is important but the knowledge of LPV-plasma-levels in patients with chronic liver disease remain uncertain. With this retrosepective analysis we want to show if there are differences in LPV-plasma-levels between patients with and without chronic liver diseases over a long-time period. LPV-plasma-levels were analysed with an HPLC-based methode. The LPV-plasma-levels over the time course in patients with chronic liver disease (n = 30) and patients without liver disease (n = 38) was evaluated. Liver function tests, CD4-cell count and HI-viral load was also correlated with liver disease. The LPV plasma-levels of n = 450 samples from 30 patients with liver disease (Hepatitis B: n = 17, Hepatitis C: n = 16, Alcoholic liver disease: n = 7) were determined over 18.7 +/- 16,3 months (1 - 48.5 months). A median of 10 samples per patient was eligible (2 - 50 samples). There are no significant differences according to liver disease in LPV-plasma levels (mean Ctrough without: 5917 +/- 4811 ng/ml, mean Ctrough with liver-disease: 6564 +/- 4517 ng/ml, p > 0.05). The intraindividual and interindividual variation of LPV-plasma levels, CD-4 increase, HI-virus suppression and liver tests in patients with and without liver disease is comparable. In this clinical setting no differences in LPV-plasma levels between patients with and without chronic liver disease could be demonstrated. LPV-therapy in patients with chronic liver disease is therefore safe. In patients with impaired liver function TDM is a helpful tool for dose adjustment.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

In seinem Beitrag „Messung von Plasmakonzentrationen antiretroviraler Arzneimittel in der HIV-Therapie“ [1] stellt v. Hentig übersichtlich und trefflich das sehr komplexe und unfangreiche Thema des Therapeutischen „Drug Monitorings“ (TDM) in der HIV-Therapie dar. Einige ergänzende Anmerkungen seien aus einem Zentrum, das sich seit über 10 Jahren mit diesem Thema beschäftigt und eine große praktische Erfahrung in der Interpretation von „Medikamentenspiegeln“ gewonnen hat, erlaubt.

A new high-performance liquid chromatographic method for the determination of tipranavir in human plasma is described.Quantitative recovery following liquid - liquid - extraction with diethylether from 100 mu l of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a Phenomenex C 18 column and UV detection at 255 nm. Linear Standard curves were obtained for concentrations ranging from 2.5 to 400 mu g/ml. The calculated intra- and inter-day coefficents of variation were below 7%.

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Objective: Many HIV-patients have a chonic liver disease due to HBV-/HCV-coinfections and/or consume of alcohol. In these patients therapy with EFV is often problematic because of NNRTI associated liver toxicity. Measurement of EFV plasmalevels and dose adjustment using TDM should be evaluated in this study Methods: EFV-plasmasamples were standardized drawn 12h after ingestion. Measurement of 576 EFV plasmalevels was performed by HPLC. EFV plasmalevels as well as ALT-, AST- and GGT-values of 64 patients treated with EFV (5206 weeks) were measured regularly. 16 patients had a HCV-coinfection, 3 had a HBV-coinfection and 5 had an concomitant alcoholic liver disease. Maximal changes of ALT-, AST- and GGT-values (Delta ALT, Delta AST, Delta GGT), CD4-/CD8 cells and HIV-RNA were registered during therapy. Dose adjustment was performed for EFV plasmalevels out of target range 1000-4000 ng/ml Results: EFV plasmalevels of 40 HIV-patients (2288 +/- 1199 ng/ml) showed no significant differences compared to plasmalevels of HIV/HCV-patients (2391 +/- 976ng/ml) or to plasmalevels of HIV/HBV-patients (1913 +/- 288ng/ml) or to those of HIV-patients with alcoholic liver disease (1702 +/- 506ng/ml). In 24 HIV-patients with underlying liver disease median Delta GGT was +25 IU/1, median Delta ALT was +13 IU/1 and median Delta AST was +8 IU/1. Dose adjustment was performed in 1 patient during study period. Increasing rates of ALT, AST- and GGT-values showed no significant differences between liver healthy HIV-patients and those with a Ever disease. 44 patients with continous EFV plasmalevels in target range reached a -viral suppression <100 c/ml during therapy. Conclusions: EFV-plasmalevels of HIV-infected patients showed no significant differences compared to EFV-plasmalevels of coinfected patients with concomitant liver disease. In those patients Delta ALT, Delta AST and Delta GGT were not significantly different than in liver-healthy HIV-patients with normal EFV-plasmaconcentrations. EFV plasmalevels in target range of 10004000 ng/ml correlate to a good viral response. One patient after dose adjustment was able to continue therapy. Using TDM EFV therapy in patients with underlying liver disease is save.

In HIV-infection, therapeutic drug monitoring (TDM) has been proposed to optimize highly active antiretroviral therapy (HAART) response. Pharmacokinetics of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz and nevirapine have been proved suitable for monitoring their plasma drug levels. In contrast, nucleoside reverse transcriptase inhibitors (NRTI) contain lack of a certain correlation between plasma levels and drug efficacy. Currently, TDM under HAART is limited by some uncertainty which pharmacokinetic predictor to prefer and on which drug concentration or range to rely on. In a therapy naive patient trial (ATHENA) on indinavir or nelfinavir based drug regimens, the study arm with use of TDM resulted in prevention of virological failure or treatment discontinuation due to drug toxicity. Current data ascribed increasing importance to TDM in ritonavir boosted PI combinations especially for lopinavir, atazanavir and fosamprenavir. Besides, further applications are proposed in selected patients groups (i.e. children, pregnancy, renal or hepatic dysfunction, weight loss) to confirm adequate drug concentrations and manage drug-drug- interactions. PI double-boosting in salvage regimens in patients with multiple NRTI associated mutations should also require TDM for handling dose adjustments, moreover, treatment experienced patients might benefit from TDM in combination with viral resistance testing. Limitations to the application of TDM are considered as non standardized procedures or techniques permitted to correlate pharmacological and virological data therefore, an approach towards standardization is needed. So far the inhibitory quotient (IQ) (necessitating phenotypical resistance testing) or the genotypic inhibitory quotient (GIQ) (referring to the number of viral mutations using a genotypic resistance test), could become increasingly important in this context. In assessing adherence, TDM allows to confirm the correct medication intake, but only the last few doses taken by a patient will be reflected. Without TDM, numerous interactions by co-administered drugs (antibiotics, antacid drugs, hypnotics, herbals, life-style drugs) turn out to possibly lead to obscure interpretations and individual medical care remains elusive.

In-vitro and limited in-vivo data suggest that uridine may be beneficial in preventing and treating the mitochondrial toxicity of pyrimidine nucleoside analogue reverse transcriptase inhibitors (NRTI). For example, the supplementation of uridine to hepatocytes exposed to pyrimidine analogues has been shown to prevent and treat mitochondrial DNA depletion and all its consequences on mitochondrial metabolism, cell survival and function [1]. Similarly, uridine also completely abrogated the lipoatrophic phenotype of adipocytes exposed to stavudine by preventing apoptosis, the loss of lipids, mtDNA depletion and mitochondrial depolarization [2]. Uridine rescued neuronal cells exposed to zalcitabine [3], and was also beneficial in both anaemia [4,5] and lipoatrophy related to zidovudine [2]. The competition of uridine or its metabolites with NRTI, either at gamma-polymerase or at enzymes responsible for NRTI activation and transport is the most plausible mechanism of action [1]. Depending on the system studied, uridine was effective at concentrations of 50–200 μM [1,4]. We have recently described an HIV patient with stavudine-related hyperlactatemia, steatohepatitis, and symptomatic elevation of creatine kinase, who rapidly improved under treatment with NucleomaxX [6]. NucleomaxX is a food supplement that contains mitocnol, a sugar cane extract with a high content (17%) of nucleosides (www.nucleomaxx.com). Because the exact effects of mitocnol consumption on the serum levels of uridine are not known in humans, we conducted a 24 h pharmacokinetic study. After ethics committee approval and informed written consent, healthy, fasting, adult human probands (four men and four women) consumed NucleomaxX by drinking 200 ml orange juice, in which one sachet (36 g) of the dietary supplement was dissolved. Baseline serum levels of uridine were measured by high-pressure liquid chromatography [7] before drinking NucleomaxX, and during the following 24 h (Fig. 1).Fig. 1: Uridine serum pharmacokinetics after oral consumption of NucleomaxX (one sachet, 36 g) at t = 0 h. Male (n = 4);female (n = 4).Mean (± SD) uridine serum levels at baseline were 5.6 ± 1.1 μM (men 5.8 μM, women 5.4 μM). After NucleomaxX consumption, uridine serum levels rose sharply and peaked after 1.3 h. The mean maximal uridine serum concentration (Cmax) was 152.0 μM (± 29.2 μM). The Cmax range was 116.0–212.0 μM. The mean Cmax in women was slightly but non-significantly higher (165.4 ± 35.8 μM) compared with men (138.6 ± 15.2 μM), possibly because of the lower body weight and body surface area of the former, (mean body weight and body surface of women: 62.3 kg and 1.71 m2) compared with the latter (men: 77.5 kg and 1.96 m2, respectively). Uridine was eliminated from the serum with an initial half-life of 2 h and a terminal half life of 11.1 h. After 8 and 24 h, the mean uridine serum levels were 19.3 μM (± 4.7 μM) and 7.5 μM (± 1.6 μM), respectively. The mean area under the curve calculated using the linear trapezoidal rule between the timepoints in the time data range was 736 μM h (± 95 μM h) and was identical between the sexes. Adverse events were not observed. We concluded that mitocnol effectively increases uridine levels in human serum. Randomized, placebo-controlled trials are currently testing NucleomaxX in order to evaluate its efficacy and safety in the prevention of NRTI-induced lipoatrophy in HIV patients. Sponsorship: This work was supported by the BMBF, Kompetenznetz HIV/AIDS (grant no. 01KI0211).