Matthijs van Luin

Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0→t for atovaquone relative to the healthy volunteers was 0.25 (0.16–0.38), 0.26 (0.17–0.41) and 0.54 (0.35–0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38–43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

Efavirenz Dose Reduction Is Safe in Patients With High Plasma Concentrations and May Prevent Efavirenz Discontinuations

Objective:To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations. Methods:HIV-infected patients with a high efavirenz plasma concentration (≥4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations. Results:One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression. Conclusions:Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.

Use of therapeutic drug monitoring in HIV disease

Purpose of review Therapeutic drug monitoring is frequently used in several European countries, and international guidelines recommend it in selected cases. We discuss the main arguments for and against therapeutic drug monitoring in HIV infection. Recent findings Accumulating evidence favours the use of therapeutic drug monitoring in the management of drug concentration-related toxicities. Interindividual variability in the pharmacokinetics of antiretroviral drugs is at least partially caused by genetic polymorphisms. Additionally, body weight, sex and ethnicity have been identified as independent predictors of pharmacokinetics. Several studies have revealed subtherapeutic drug concentrations in children who were treated in accordance with the label information, which is in favour of therapeutic drug monitoring in children. The inhibitory quotient concept has been further explored, but more work is needed to justify full implementation into routine clinical practice. A limitation of therapeutic drug monitoring is the significant intraindividual variability in protease inhibitor concentrations. Furthermore, there is a lack of sufficiently powered randomized controlled trials that assess the use of routine therapeutic drug monitoring for current first-line antiretroviral drugs. Summary Although routine therapeutic drug monitoring cannot be recommended for current first-line antiretroviral drugs, there are many frequently encountered clinical situations in which therapeutic drug monitoring provides valuable information.

The effect of raltegravir on the glucuronidation of lamotrigine.

The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48‐hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration‐time curve (AUC0→48) and peak plasma concentration (Cmax) for raltegravir + lamotrigine versus lamotrigine alone were 0.99 (0.96–1.01) and 0.94 (0.89–0.99), respectively. The mean ratio of the AUC0→48 of lamotrigine‐2N‐glucuronide to lamotrigine was similar when lamotrigine was taken alone (0.35) or when taken with raltegravir (0.36). Raltegravir does not influence the glucuronidation of lamotrigine.

Adherence to HIV therapeutic drug monitoring guidelines in The Netherlands

Background: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005. Methods: From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM. Results: The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM. Conclusion: The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Measuring plasma concentrations of ribavirin: first report from a quality control program

To the Editors: A chronic hepatitis C virus (HCV) infection is nowadays treated with combination therapy of novel direct-acting antivirals. These drugs are very effective, and high sustained virological response rates are achieved in patients without cirrhosis (.90%). Cirrhotic patients are more difficult to treat, which could be due to physiological changes caused by scarring of the liver. Therefore, ribavirin is added to direct-acting antiviral therapy, which improves HCV treatment response and gives an opportunity to shorten treatment duration from 24 to 12 weeks. Ribavirin has a strong concentration–effect relationship, and therapeutic drug monitoring (TDM) can be used to individualize the dose of ribavirin. Therefore, several laboratories developed ribavirin assays. These methods are generally validated internally for validation parameters such as accuracy, precision, selectivity, sensitivity, reproducibility, and stability according to international guidelines. To ensure the accuracy of these bioanalytical methods and to alert laboratories to previously undetected problems, we developed an international external quality control (QC) or proficiency testing (PT) program for measurement of ribavirin. The aim of this report was to describe the results of the first year of this ribavirin PT program. In 2015, we dispatched 2 samples per round (2 rounds in total) to the participating laboratories. For these samples, bovine serum was spiked with low and high concentrations of ribavirin. These samples were freeze dried and were shipped by regular mail. For 2 participants, the samples were shipped on dry ice because they participated in another program requiring shipment on dry ice. The concentrations chosen resembled the range of concentrations measured in patients treated with a normal dose of ribavirin (patient weight ,75 kg = 1000 mg/d and

A design for external quality assessment for the analysis of thiopurine drugs: pitfalls and opportunities

75 kg = 1200 mg/d). The target range for ribavirin plasma concentrations at steady state is 2.2–3.6 mg/L. Details of similar programs have been described previously. Participants were informed about their performance in measuring ribavirin concentrations. Accuracy was considered to be acceptable if measurements were within the 80%– 120% limits of the spiked (weighed-in) “expert” concentrations. This 20% threshold was based on guidelines for method validation for bioanalysis of drugs with 20% deviations used as fixed criterion for inaccuracy at the lowest level of quantification and on maximum allowable error specifications for drug measurements according to the US Clinical Laboratory Improvement Amendments (CLIA) of 1988. Eight laboratories participated in the program, of which 2 participants completed one round. Most participants (n = 7) used liquid chromatography with mass spectrometry detection to determine ribavirin concentrations. One center used high-performance liquid chromatography with an ultraviolet detector. In round 1, 81% of the samples (ie, 13 of 16 samples) were determined accurately, and the variation in accuracy of samples with low concentrations was 86%–336%. The samples spiked with high ribavirin concentrations varied from 55% to 160% in accuracy (Table 1 and Fig. 1). In round 2, a total of 75% samples (ie, 9 of 12) were determined accurately within 80%–120% of the weighed-in concentrations. Accuracy for samples with low and high concentrations varied from 97% to 303% and from 97% to 148%, respectively. The median inaccuracy for all measurements was 6.1% (range: 0.8%– 236.2%). It was 6.7% (range: 1.6%– 236.2%) and 6.1% (range: 0.8%–60.4%) for low and high ribavirin concentrations, respectively. Of the 8 participating laboratories, 5 had all samples analyzed within 80%– 120% limits of the weighed-in concentrations, 3 reported at least one inaccurate result, of which one participant reported all 4 samples inaccurately (.120%). The aim of a PT program is to provide external validation of bioanalytical assays to assure and improve quality. Participating laboratories were informed about their performance and their ability to measure the correct analyte concentrations. This may help them to improve their laboratory performance. The analysis of this small sample set showed that 6/28 of the ribavirin samples were measured inaccurately, which was in line with first rounds of

Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin.

Abstract Background For the analysis of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6-MMPR), no external quality assessment scheme (EQAS) is currently available and no quality control samples can be made because of the absence of pure substances. An experimental design is tested to compare laboratory analytical results. Methods In this EQAS, participating laboratories were asked to select patient samples from their routine analysis and exchange these with a coupled laboratory. Because of large differences in results between laboratories, all standard operating procedures were reviewed, revealing that the origin of these differences could be in the method of hydrolysis and the preparation of calibrators. To investigate the contribution of the calibrators to these differences, one participating laboratory was asked to prepare a batch of calibrators to be shipped to the participating laboratories for analysis. Results Results for 6-TGN differed more between laboratories, compared with results for 6-MMPR. For 6-TGN and 6-MMPR 43% and 24% of the results, respectively, were out of the 80%–120% range. When correcting the results from the exchange of the patient samples with the results of the calibrators, the mean absolute difference for 6-TGN improved from 24.8% to 16.3% (p<0.001), while the results for 6-MMPR worsened from 17.3% to 20.0% (p=0.020). Conclusions This first EQAS for thiopurine drugs shows that there is a difference between laboratories in the analysis of 6-TGN, and to a lesser extent in the analysis of 6-MMPR. This difference for 6-TGN can partially be explained by the use of in-house-prepared calibrators that differ among the participants.