Rob Ter Heine

Meander Medisch Centrum, Amersfoort, Utrecht, Netherlands

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Publications (30)98.28 Total impact

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    ABSTRACT: Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modeling. Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (p<0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to separately assess the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-estrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
    British Journal of Clinical Pharmacology 04/2014; · 3.58 Impact Factor
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    ABSTRACT: Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented.
    International Journal of Pharmaceutics 02/2014; · 3.99 Impact Factor
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    ABSTRACT: Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.
    Journal of child neurology 05/2013; · 1.59 Impact Factor
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    ABSTRACT: BACKGROUND: In HIV-infected patients therapeutic drug monitoring (TDM) of antiretroviral drugs is recommended in special populations and specific situations to optimize therapy. Currently, TDM is performed via measurement of drug plasma concentrations. However, dried blood spots (DBS) may offer a patient friendly and cost effective alternative. Therefore, this proof of concept study assessed the feasibility of TDM of antiretroviral drugs using DBS with sampling at home. METHODS: Included patients were instructed to sample three DBS just before drug intake at three consecutive days at home and one DBS sample together with their routine venous sampling. All samples were analyzed using liquid chromatography coupled to tandem mass spectrometry. Feasibility was investigated with a questionnaire and via determination of the calculated plasma trough concentrations. RESULTS: In total, 50 patients (48 male, mean age 50 (range 29-69 years)) have been included of whom most were virologically and immunologically well controlled. In total, 200 DBS were collected of whom 87.5% were suitable for analysis. The questionnaire showed most patients (68%) successfully obtained the first DBS and 51% preferred DBS over plasma sampling. Plasma trough concentrations could adequately be determined from dried blood spots. CONCLUSIONS: This proof of concept study confirms the feasibility of TDM of antiretroviral drugs using dried blood spots with sampling at home, thereby opening the possibility to obtain trough concentrations at home in populations where venous sampling is difficult.
    Antiviral therapy 12/2012; · 3.07 Impact Factor
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    ABSTRACT: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. Erlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.
    Lung cancer (Amsterdam, Netherlands) 11/2011; 75(3):391-7. · 3.14 Impact Factor
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    ABSTRACT: Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
    Journal of Pharmaceutical Sciences 06/2011; 100(6):2508-15. · 3.13 Impact Factor
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    ABSTRACT: We present 2 human immunodeficiency virus-infected patients with tenofovir disoproxil fumarate-induced Fanconi syndrome, leading to osteomalacia. Intracellular tenofovir diphosphate levels were measured in 1 patient and were found to be very high, with plasma tenofovir levels just slightly elevated. Fibroblast growth factor-23, a phosphaturic hormone, was decreased in both patients and is therefore unlikely to have a pathophysiological role in this pathology. The different potential factors contributing to the development of tenofovir-related kidney proximal tubular dysfunction are discussed and the data presented may help to further elucidate its pathogenesis.
    Scandinavian Journal of Infectious Diseases 05/2011; 43(10):821-6. · 1.71 Impact Factor
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    ABSTRACT: Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir. DBS concentrations were measured in 11 HIV-infected patients using LC-MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study. DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV-infected patients.
    Bioanalysis 05/2011; 3(10):1093-7. · 3.25 Impact Factor
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    ABSTRACT: There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent. Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole. Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally. More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.
    British Journal of Clinical Pharmacology 12/2010; 70(6):908-11. · 3.58 Impact Factor
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    ABSTRACT: We previously developed a method for the simultaneous determination of the human immunodeficiency protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir, the active nelfinavir metabolite M8 the non-nucleoside reverse transcriptase inhibitors efavirenz, nevirapine and etravirine and the internal standards dibenzepine, (13)C(6)-efavirenz, D5-saquinavir and D6-indinavir in plasma using liquid chromatography coupled with tandem mass spectrometry with a Sciex API3000 triple quadrupole mass spectrometer and an analytical run time of only 10 min. We report the transfer of this method from the API3000 to a supposedly less sensitive Sciex API365 mass spectrometer. We describe the steps that were undertaken to optimize the sensitivity and validation of the method that we transferred. We showed that transfer of a method to a putative less sensitive detector did not necessarily result in a less sensitive assay, and this method can be applied in laboratories where older mass spectrometers are available. Ultimately, the performance of the method was validated. Accuracy and precision was within 87%-110% and <13%, respectively. No notable loss in selectivity was observed.
    Clinical Chemistry and Laboratory Medicine 08/2010; 48(8):1153-5. · 3.01 Impact Factor
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    ABSTRACT: Background and purpose:  Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P-glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir and the relative importance of intestinal and hepatic metabolism. We also evaluated whether ritonavir increases lopinavir oral bioavailability by inhibition of CYP3A, ABCB1 and/or ABCC2.Experimental approach:  Lopinavir transport was measured in Madin-Darby canine kidney cells expressing ABCB1 or ABCC2. Oral lopinavir kinetics (+/− ritonavir) was studied in mice with genetic deletions of Cyp3a, Abcb1a/b and/or Abcc2, or in transgenic mice expressing human CYP3A4 exclusively in the liver and/or intestine.Key results:  Lopinavir was transported by ABCB1 but not by ABCC2 in vitro. Lopinavir area under the plasma concentration – time curve (AUC)oral was increased in Abcb1a/b−/− mice (approximately ninefold vs. wild-type) but not in Abcc2−/− mice. Increased lopinavir AUCoral (>2000-fold) was observed in cytochrome P450 3A knockout (Cyp3a−/−) mice compared with wild-type mice. No difference in AUCoral between Cyp3a−/− and Cyp3a/Abcb1a/b/Abcc2−/− mice was observed. CYP3A4 activity in intestine or liver, separately, reduced lopinavir AUCoral (>100-fold), compared with Cyp3a−/− mice. Ritonavir markedly increased lopinavir AUCoral in all CYP3A-containing mouse strains.Conclusions and implications:  CYP3A was the major determinant of lopinavir pharmacokinetics, far more than Abcb1a/b. Both intestinal and hepatic CYP3A activity contributed importantly to low oral bioavailability of lopinavir. Ritonavir increased lopinavir bioavailability primarily by inhibiting CYP3A. Effects of Abcb1a/b were only detectable in the presence of CYP3A, suggesting saturation of Abcb1a/b in the absence of CYP3A activity.
    British Journal of Pharmacology 06/2010; 160(5):1224 - 1233. · 5.07 Impact Factor
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    ABSTRACT: To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l(-1) in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance.
    British Journal of Clinical Pharmacology 05/2010; 69(5):475-83. · 3.58 Impact Factor
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    ABSTRACT: Emtricitabine (FTC) and tenofovir (TFV) are widely used antiviral agents that require intracellular phosphorylation to become active. This article describes the development and validation of an assay for the simultaneous quantification of FTC mono-, di- and triphosphate (FTC-MP, -DP and -TP), TFV and TFV mono- and diphosphate (TFV-MP and -DP) in peripheral blood mononuclear cells. Reference compounds and internal standards were obtained by thermal degradation of FTC-TP, TFV-DP, stable isotope-labeled TFV-DP and stable isotope-labeled cytosine triphosphate. Cells were lysed in methanol:water (70:30, v/v) and the extracted nucleotides were analyzed using weak anion-exchange chromatography coupled with tandem mass spectrometry. Calibration ranges in PBMC lysate from 0.727 to 36.4, 1.33 to 66.4 and 1.29 to 64.6 nM for FTC-MP, FTC-DP and FTC-TP and from 1.51 to 75.6, 1.54 to 77.2 and 2.54 to 127 nM for TFV, TFV-MP and TFV-DP, respectively, were validated. Accuracies were within -10.3 and 16.7% deviation at the lower limit of quantification at which the coefficients of variation were less than 18.2%. At the other tested levels accuracies were within -14.3 and 9.81% deviation and the coefficients of variation lower than 14.7%. The stability of the compounds was assessed under various analytically relevant conditions. The method was successfully applied to clinical samples.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 03/2010; 878(7-8):621-7. · 2.78 Impact Factor
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    Journal of the International AIDS Society 01/2010; 13. · 3.94 Impact Factor
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    R ter Heine, J H Beijnen, A D R Huitema
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    ABSTRACT: Therapeutic drug monitoring is a way to pharmacokinetically guide drug therapy to assure a certain exposure to a drug when this exposure is related to treatment effectiveness or toxicity. Routinely, drug concentrations are measured in plasma obtained by venipuncture. However, venous sampling is difficult in some populations, such as neonates and patients suffering from phlebitis, and there may be logistical challenges, for example when nonhospital-based sampling is warranted (e.g., resource-limited settings). A proper bioanalytical method is crucial for measurements of drug level matrices suitable for patient-friendly drug monitoring. Special attention must be paid to bioanalytical methods in these patient-friendly matrices, since specific matrix-associated issues may have important implications. In this review, we will discuss these issues and give an overview of published bioanalytical methods with a focus on patient-friendly drug monitoring of antiretroviral drugs, where dried blood spots, hair and saliva have been the most important matrices for patient-friendly therapeutic drug monitoring. Furthermore, we will point out considerations for proper assay development and validation.
    Bioanalysis 10/2009; 1(7):1329-38. · 3.25 Impact Factor
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    ABSTRACT: To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer. A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 +/- 1.5 and 2.8 +/- 1.4 mg/h/L, respectively, compared with 1.9 +/- 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% +/- 90% and 161% +/- 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated. Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.
    Clinical Cancer Research 07/2009; 15(12):4228-33. · 7.84 Impact Factor
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    ABSTRACT: Atazanavir is a commonly prescribed protease inhibitor for treatment of HIV-1 infection. Thus far, only limited data are available on the in vivo metabolism of the drug. Three systemic circulating metabolites have been reported, but their chemical structures have not been released publicly. Atazanavir metabolites may contribute to its effectiveness but also to its toxicity and interactions. Thus, there is a need for extensive metabolic profiling of atazanavir. Our goals were to screen and identify previously unknown atazanavir metabolites and to develop a sensitive metabolite profiling method in plasma. Five atazanavir metabolites were detected and identified in patient samples using liquid chromatography coupled to linear ion trap mass spectrometry: one N-dealkylation product (M1), two metabolites resulting from carbamate hydrolysis (M2 and M3), a hydroxylated product (M4), and a keto-metabolite (M5). For sensitive semiquantitative analysis of the metabolites in plasma, the method was transferred to liquid chromatography coupled to triple quadrupole mass spectrometry. In 12 patient samples, all the metabolites could be detected, and possible other potential atazanavir keto-metabolites were found. Atazanavir metabolite levels were positively correlated with atazanavir levels, but interindividual variability was high. The developed atazanavir metabolic screening method can now be used for further clinical pharmacological research with this antiretroviral agent.
    Drug metabolism and disposition: the biological fate of chemicals 07/2009; 37(9):1826-40. · 3.74 Impact Factor
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    ABSTRACT: In this study, we present a case of renal failure in a patient who was on a tenofovir-containing regimen, resulting in extremely high tenofovir exposure and prolonged tenofovir monotherapy. We considered this case report important because exposure to tenofovir monotherapy might have consequences for future discontinuation strategies in cases of renal failure.
    Antiviral therapy 02/2009; 14(2):299-301. · 3.07 Impact Factor
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    ABSTRACT: For pharmacokinetic monitoring, measurement of antiretroviral agents in plasma is the gold standard. However, human immunodeficiency virus protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) exert their action within the infected cell. Cell-associated concentrations may therefore more adequately reflect therapy outcome. Therefore, for the quantification of nine PIs (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir), 1 active PI metabolite (nelfinavir M8) and 2 NNRTIs (efavirenz and nevirapine) in lysate of peripheral blood mononuclear cells (PBMCs) an assay was developed and validated, using liquid chromatography coupled with tandem mass spectrometry. Analytes were extracted from a PBMC pellet by means of a one-step extraction with 50% methanol containing the internal standards D6-indinavir, D5-saquinavir, 13C6-efavirenz and dibenzepine. Chromatographic separation was performed on a reversed phase C18 column (150mmx2.0mm, particle size 5microm) with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.25mL/min. The analytical run time was 10min. The triple quadrupole mass spectrometer was operated in the positive ion-mode and multiple reaction monitoring was used for drug quantification. The method was validated over a range of 1-500ng/mL in PBMC lysate for all analytes. The method was proven to be specific, accurate, precise and robust. The mean precision and accuracy was less than +/-12% at all concentration levels. Using the developed assay and a previously developed assay for these analytes in plasma, the relationship between plasma and intracellular pharmacokinetics and their relationship with therapy outcome can now be determined.
    Journal of Chromatography B 02/2009; 877(5-6):575-80. · 2.49 Impact Factor
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    R. ter Heine
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    ABSTRACT: The aims of all studies described in this thesis were to develop new bioanalytical and more patient friendly methods for studying the clinical pharmacology of antiretroviral drugs and to ultimately improve antiretroviral treatment.
    01/2009;