Rob Aarnoutse | Radboudumc Nijmegen - The Netherlands (original) (raw)
Papers by Rob Aarnoutse
British Journal of Clinical Pharmacology, 2003
This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements ... more This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. Methods Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2000/200 mg (group 1), 2000/ 400 mg (group 2) or 2500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. Results Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC 24h values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h C min concentrations of nelfinavir were 0.76 mg l -1 , 0.43 mg l -1 and 0.47 mg l -1 , respectively. Coadministration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC 24h and C min values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1250 mg BID without ritonavir). In the 2000/200 mg group, seven out of eight subjects had a C min value of nelfinavir plus M8 above a threshold of 1.0 mg l -1 . Administration of the combinations with a light breakfast resulted in significant decreases in the AUC 24h and C min of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the C min of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined) . Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). Conclusions Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.
Antimicrobial Agents and Chemotherapy, 2006
Clinical Infectious Diseases, 2007
BACKGROUND: The long duration of the current tuberculosis (TB) treatment is demanding and warrant... more BACKGROUND: The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be
Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2005
A reversed phase high performance liquid chromatography method was developed for the simultaneous... more A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength
Clinical experience with the combined use of lopinavir/ritonavir and rifampicin
Aids, 2009
Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated... more Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse
The effect of nevirapine on the pharmacokinetics of indinavir/ritonavir 800/100 mg BID
Jaids-journal of Acquired Immune Deficiency Syndromes, 2004
Antimicrobial Agents and Chemotherapy, 2009
An international interlaboratory proficiency testing program for the measurement of antifungal dr... more An international interlaboratory proficiency testing program for the measurement of antifungal drugs was initiated in 2007. This first round was limited to azole antifungals: fluconazole, itraconazole and hydroxyitraconazole, voriconazole, and posaconazole. The results demonstrate the need for and utility of an ongoing proficiency testing program to further improve the analytical methods for routine patient management and clinical research.
Antimicrobial Agents and Chemotherapy, 2009
One-third of the world population is infected with Mycobac- terium tuberculosis (MTB) and hence a... more One-third of the world population is infected with Mycobac- terium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of
Clinical Pharmacology & Therapeutics, 2005
Objective: In the treatment of human immunodeficiency virus infection, the protease inhibitor rit... more Objective: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is
Summary: Objective: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhi... more Summary: Objective: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhibitors outside of which random plasma concentrations reflect partial compliance or noncompliance. In the absence of a gold standard for measuring com- pliance and to avoid complex techniques, measuring plasma concentrations may be an objective and easy way to check noncompliance.
International journal of antimicrobial agents, 2015
Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), the... more Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), there is an urgent need for new TB drugs or for compounds that improve the efficacy of currently used drugs. In this study, time-kill kinetics of SILA-421 as a single drug and in combination with isoniazid (INH), rifampicin (RIF), moxifloxacin (MXF) or amikacin (AMK) against Mycobacterium tuberculosis were assessed. Therapeutic efficacy in vivo in a mouse TB model was also studied. Further in vitro analysis was performed with a RIF-susceptible and RIF-resistant strains of M. tuberculosis. When used as a single drug, SILA-421 in vitro showed concentration-dependent and time-dependent bactericidal activity. SILA-421 also enhanced the activity of INH and RIF, resulting in synergy in the case of INH. Emergence of INH resistance following exposure to INH can be prevented by the addition SILA-421. SILA-421 had no additional value in combination with MXF or AMK. Furthermore, SILA-421 enhanced the ...
Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis
Antimicrobial Agents and Chemotherapy, 2015
Rifampin together with isoniazid has been the backbone of the current first-line treatment of tub... more Rifampin together with isoniazid has been the backbone of the current first-line treatment of tuberculosis (TB). The Area Under the concentration-time Curve from 0 to 24 hours (AUC0-24h) to MIC ratio is the best predictive pharmacokinetic-pharmacodynamic parameter for efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24h.Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n=1000).Geometric mean AUC0-24h was 41.5 (range 13.5-117) mg*h/L. Median Tmax was 2.2 hours, ranging from 0.4 up to 5.7 hours. This wide range indicates that only obtaining a concentration level at 2 hours (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 hours post dosing was considered clinically suitable with r(2) 0.96, root mean squared error 13.2%, and prediction bias -0.4%.This study showed that rifampin AUC0-24h in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 hours.
Xanthine oxidase inhibition by allopurinol increases in vitro pyrazinamide-induced hepatotoxicity in HepG2 cells
Drug and Chemical Toxicology, 2010
Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the m... more Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in vitro pyrazinamide toxicity in HepG2 cells, which suggests that the hydroxy metabolites of pyrazinamide are probably not fully responsible for pyrazinamide-induced
An interlaboratory quality control programme for the measurement of tuberculosis drugs
The European respiratory journal, Jan 16, 2015
Shorter moxifloxacin-based regimens for drug-sensitive tuberculosis
The New England journal of medicine, Jan 5, 2015
The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers
Clinical pharmacology and therapeutics, 2002
This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics o... more This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavi...
Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected Patients
Clinical Pharmacology & Therapeutics, 2008
This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotei... more This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.
Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis
International journal of antimicrobial agents, Jan 7, 2015
Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculo... more Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2...
Tuberculosis, 2014
Objectives: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), ... more Objectives: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), in vitro and in vivo as a single drug and in combination with tuberculosis (TB) drugs. Methods: The in vitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. In vivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment. Results: In vitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy. Conclusions: Thioridazine is bactericidal towards Mtb in vitro, irrespective the mycobacterial growth rate and results in enhanced activity of the standard regimen. The in vitro activity of thioridazine in potentiating isoniazid and rifampicin is not reflected by improved therapeutic efficacy in a murine TB-model.
Poor Performance of Laboratories Assaying Newly Developed Antiretroviral Agents
Therapeutic Drug Monitoring, 2014
The International Interlaboratory Quality Control PROGRAM for Therapeutic Drug Monitoring of Anti... more The International Interlaboratory Quality Control PROGRAM for Therapeutic Drug Monitoring of Antiretroviral Drugs in Human Plasma/Serum was initiated in 1999. We have previously published our experience during the first 10 years of the PROGRAM. Since 2010, 3 newly developed antiretroviral agents have been added to the darunavir, etravirine, and raltegravir. The objective of this analysis is to describe the performance of participating laboratories measuring these newer agents in 2011-2012. Each year, laboratories received 2 blind samples of human plasma/serum spiked with a low (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.0 mg/L), medium (1.0-5.0 mg/L), or high (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5.0 mg/L) concentration of these drugs. Laboratory results were standardized to percentages with reference to the nominal (true) concentration. Any result that deviated more than 20% of the nominal values was defined as inaccurate. The numbers of laboratories that participated by the end of 2012 were 44 for darunavir, 28 for etravirine, and 30 for raltegravir. A total of 357 results were evaluable for analysis. Of these, 64 (17.9%) results were reported with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20% deviation, so &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;inaccurate&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; (7.6% too low, 10.4% too high). The proportion of inaccurate results in 2011 was 21.3% for darunavir, 31.0% for etravirine, and 26.3% for raltegravir; in 2012, these figures improved to 8.1%, 23.2%, and 8.3% for darunavir, etravirine, and raltegravir, respectively. Taking darunavir as the reference, performance for etravirine was significantly lower [odds ratio = 0.462, 95% confidence interval: 0.246-0.866, P = 0.016] and performance for raltegravir was not significantly different. Low concentrations were significantly more frequently reported as inaccurate than medium or high concentrations: 28.6% versus 10.6% versus 8.8%, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Laboratories that used Liquid Chromatography with tandem Mass Spectrometry did not perform better than those using High Performance Liquid Chromatography/Ultrarapid Performance Liquid Chromatography: 41 inaccurate results in 200 samples (20.5%) versus 23 in 157 samples (14.6%, P = 0.154). Multiple logistic regression revealed that the concentration range was the only significant predictor of inaccurate results. The lower range of concentrations performed worse than medium or high concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Laboratories continue to have problems with adequately measuring low plasma concentrations of antiretroviral agents. This is particularly a problem for some of the newer antiretroviral agents with plasma concentrations in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.0 mg/L range, such as etravirine and raltegravir.
British Journal of Clinical Pharmacology, 2003
This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements ... more This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. Methods Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2000/200 mg (group 1), 2000/ 400 mg (group 2) or 2500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. Results Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC 24h values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h C min concentrations of nelfinavir were 0.76 mg l -1 , 0.43 mg l -1 and 0.47 mg l -1 , respectively. Coadministration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC 24h and C min values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1250 mg BID without ritonavir). In the 2000/200 mg group, seven out of eight subjects had a C min value of nelfinavir plus M8 above a threshold of 1.0 mg l -1 . Administration of the combinations with a light breakfast resulted in significant decreases in the AUC 24h and C min of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the C min of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined) . Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). Conclusions Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.
Antimicrobial Agents and Chemotherapy, 2006
Clinical Infectious Diseases, 2007
BACKGROUND: The long duration of the current tuberculosis (TB) treatment is demanding and warrant... more BACKGROUND: The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be
Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2005
A reversed phase high performance liquid chromatography method was developed for the simultaneous... more A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength
Clinical experience with the combined use of lopinavir/ritonavir and rifampicin
Aids, 2009
Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated... more Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse
The effect of nevirapine on the pharmacokinetics of indinavir/ritonavir 800/100 mg BID
Jaids-journal of Acquired Immune Deficiency Syndromes, 2004
Antimicrobial Agents and Chemotherapy, 2009
An international interlaboratory proficiency testing program for the measurement of antifungal dr... more An international interlaboratory proficiency testing program for the measurement of antifungal drugs was initiated in 2007. This first round was limited to azole antifungals: fluconazole, itraconazole and hydroxyitraconazole, voriconazole, and posaconazole. The results demonstrate the need for and utility of an ongoing proficiency testing program to further improve the analytical methods for routine patient management and clinical research.
Antimicrobial Agents and Chemotherapy, 2009
One-third of the world population is infected with Mycobac- terium tuberculosis (MTB) and hence a... more One-third of the world population is infected with Mycobac- terium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of
Clinical Pharmacology & Therapeutics, 2005
Objective: In the treatment of human immunodeficiency virus infection, the protease inhibitor rit... more Objective: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is
Summary: Objective: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhi... more Summary: Objective: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhibitors outside of which random plasma concentrations reflect partial compliance or noncompliance. In the absence of a gold standard for measuring com- pliance and to avoid complex techniques, measuring plasma concentrations may be an objective and easy way to check noncompliance.
International journal of antimicrobial agents, 2015
Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), the... more Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), there is an urgent need for new TB drugs or for compounds that improve the efficacy of currently used drugs. In this study, time-kill kinetics of SILA-421 as a single drug and in combination with isoniazid (INH), rifampicin (RIF), moxifloxacin (MXF) or amikacin (AMK) against Mycobacterium tuberculosis were assessed. Therapeutic efficacy in vivo in a mouse TB model was also studied. Further in vitro analysis was performed with a RIF-susceptible and RIF-resistant strains of M. tuberculosis. When used as a single drug, SILA-421 in vitro showed concentration-dependent and time-dependent bactericidal activity. SILA-421 also enhanced the activity of INH and RIF, resulting in synergy in the case of INH. Emergence of INH resistance following exposure to INH can be prevented by the addition SILA-421. SILA-421 had no additional value in combination with MXF or AMK. Furthermore, SILA-421 enhanced the ...
Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis
Antimicrobial Agents and Chemotherapy, 2015
Rifampin together with isoniazid has been the backbone of the current first-line treatment of tub... more Rifampin together with isoniazid has been the backbone of the current first-line treatment of tuberculosis (TB). The Area Under the concentration-time Curve from 0 to 24 hours (AUC0-24h) to MIC ratio is the best predictive pharmacokinetic-pharmacodynamic parameter for efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24h.Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n=1000).Geometric mean AUC0-24h was 41.5 (range 13.5-117) mg*h/L. Median Tmax was 2.2 hours, ranging from 0.4 up to 5.7 hours. This wide range indicates that only obtaining a concentration level at 2 hours (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 hours post dosing was considered clinically suitable with r(2) 0.96, root mean squared error 13.2%, and prediction bias -0.4%.This study showed that rifampin AUC0-24h in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 hours.
Xanthine oxidase inhibition by allopurinol increases in vitro pyrazinamide-induced hepatotoxicity in HepG2 cells
Drug and Chemical Toxicology, 2010
Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the m... more Despite the important role of pyrazinamide in tuberculosis treatment, little is known about the mechanism of pyrazinamide-induced hepatotoxicity. We inhibited xanthine oxidase in HepG2 cells by using a nontoxic concentration of allopurinol, a well-known xanthine-oxidase inhibitor. This increased in vitro pyrazinamide toxicity in HepG2 cells, which suggests that the hydroxy metabolites of pyrazinamide are probably not fully responsible for pyrazinamide-induced
An interlaboratory quality control programme for the measurement of tuberculosis drugs
The European respiratory journal, Jan 16, 2015
Shorter moxifloxacin-based regimens for drug-sensitive tuberculosis
The New England journal of medicine, Jan 5, 2015
The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers
Clinical pharmacology and therapeutics, 2002
This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics o... more This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavi...
Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected Patients
Clinical Pharmacology & Therapeutics, 2008
This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotei... more This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.
Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis
International journal of antimicrobial agents, Jan 7, 2015
Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculo... more Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2...
Tuberculosis, 2014
Objectives: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), ... more Objectives: Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), in vitro and in vivo as a single drug and in combination with tuberculosis (TB) drugs. Methods: The in vitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. In vivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment. Results: In vitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy. Conclusions: Thioridazine is bactericidal towards Mtb in vitro, irrespective the mycobacterial growth rate and results in enhanced activity of the standard regimen. The in vitro activity of thioridazine in potentiating isoniazid and rifampicin is not reflected by improved therapeutic efficacy in a murine TB-model.
Poor Performance of Laboratories Assaying Newly Developed Antiretroviral Agents
Therapeutic Drug Monitoring, 2014
The International Interlaboratory Quality Control PROGRAM for Therapeutic Drug Monitoring of Anti... more The International Interlaboratory Quality Control PROGRAM for Therapeutic Drug Monitoring of Antiretroviral Drugs in Human Plasma/Serum was initiated in 1999. We have previously published our experience during the first 10 years of the PROGRAM. Since 2010, 3 newly developed antiretroviral agents have been added to the darunavir, etravirine, and raltegravir. The objective of this analysis is to describe the performance of participating laboratories measuring these newer agents in 2011-2012. Each year, laboratories received 2 blind samples of human plasma/serum spiked with a low (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.0 mg/L), medium (1.0-5.0 mg/L), or high (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5.0 mg/L) concentration of these drugs. Laboratory results were standardized to percentages with reference to the nominal (true) concentration. Any result that deviated more than 20% of the nominal values was defined as inaccurate. The numbers of laboratories that participated by the end of 2012 were 44 for darunavir, 28 for etravirine, and 30 for raltegravir. A total of 357 results were evaluable for analysis. Of these, 64 (17.9%) results were reported with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;20% deviation, so &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;inaccurate&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; (7.6% too low, 10.4% too high). The proportion of inaccurate results in 2011 was 21.3% for darunavir, 31.0% for etravirine, and 26.3% for raltegravir; in 2012, these figures improved to 8.1%, 23.2%, and 8.3% for darunavir, etravirine, and raltegravir, respectively. Taking darunavir as the reference, performance for etravirine was significantly lower [odds ratio = 0.462, 95% confidence interval: 0.246-0.866, P = 0.016] and performance for raltegravir was not significantly different. Low concentrations were significantly more frequently reported as inaccurate than medium or high concentrations: 28.6% versus 10.6% versus 8.8%, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Laboratories that used Liquid Chromatography with tandem Mass Spectrometry did not perform better than those using High Performance Liquid Chromatography/Ultrarapid Performance Liquid Chromatography: 41 inaccurate results in 200 samples (20.5%) versus 23 in 157 samples (14.6%, P = 0.154). Multiple logistic regression revealed that the concentration range was the only significant predictor of inaccurate results. The lower range of concentrations performed worse than medium or high concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Laboratories continue to have problems with adequately measuring low plasma concentrations of antiretroviral agents. This is particularly a problem for some of the newer antiretroviral agents with plasma concentrations in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1.0 mg/L range, such as etravirine and raltegravir.