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Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open-label microdosing study, a gemcitabine microdose (100 µg) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg/m 2 ) on day 2. Gemcitabine and its metabolite 2',2'-difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography-mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration-time curve (AUC 0-8 ) of gemcitabine after microdosing was 0.00074 h·mg/L and after therapeutic dosing was 16 h·mg/L. The mean AUC 0-8 of dFdU following the microdose and therapeutic dose were 0.022 h·mg/L and 169 h·mg/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2-fold of the exposure following a microdose, when linearly extrapolated to 1250 mg/m 2 . However, the shape of the concentration-time curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC 0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m 2 . Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case., (© 2020, The American College of Clinical Pharmacology.)

Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients., (© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

This study aimed to predict the area under the curve (AUC) of the initial busulfan dose using a test dose with the sparse sampling scheme in adult patients who underwent hematopoietic cell transplant. A test dose of 0.8 mg/kg busulfan was used 2 days before twice-daily intravenous busulfan-based conditioning regimens were administered. The AUC and the clearance (CL) were calculated for both the test dose and the first dose (AUC T , CL T , AUC 1, and CL 1 ) by noncompartmental analysis. The sparse sampling schemes of the test dose were developed by Bayesian method based on the population pharmacokinetic model. The optimal sparse sampling schemes were determined by evaluating the mean prediction error, the root mean square error, the absolute mean prediction error, and Bland-Altman plot. The mean AUC 1 was 7.20 ± 1.48 mg • h/L, which ranged from 4.70 to 9.46 mg • h/L. The AUC 1 was below the therapeutic concentration of 7.38 mg • h/L in 45% (9 of 20) of the patients. The CL T of 3.05 ± 0.56 mL/min/kg was not significantly different with the CL 1 of 3.03 ± 0.69 mL/min/kg (P = .901). A sampling scheme at 2 and 6 hours after the test dose was developed to predict the AUC T (mean prediction error of 1.64%, root mean square error of 6.17%, and absolute mean prediction error of 4.94%). Additionally, the Bland-Altman plot showed that the 2-sampling scheme provided an acceptably accurate prediction of the AUC 1 . A test dose with a 2-sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients., (© 2018, The American College of Clinical Pharmacology.)

Background: Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD). Because hypercalcemia has been the most worrisome calcitriol-related adverse event, the less hypercalcemic agent paricalcitol may be preferred for further investigation., Methods: The authors undertook a phase 1 study of gemcitabine in combination with escalating doses of paricalcitol administered weekly intravenously in patients with advanced cancers. A standard 3+3 dose escalation schema was used. Pharmacokinetic assessment of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was performed. Pharmacodynamic assessment of paricalcitol was performed by measurement of CDD activity in peripheral blood mononuclear cells., Results: A total of 44 patients were enrolled. Somnolence was the main dose-limiting toxicity. The highest dose of paricalcitol administered was 10.5 µg/kg. Hypercalcemia was infrequent and mild in severity. Paricalcitol did not appear to affect the pharmacokinetics of gemcitabine and dFdU. Evaluation of CDD activity was available for 9 patients; no clear trend for CDD activity after treatment with paricalcitol was established. The overall response rate was 4%; the rate of disease control was 67% in patients who were pretreated with gemcitabine. Progression-free and overall survival were 3.4 months and 6.5 months, respectively., Conclusions: Paricalcitol can be administered safely in doses up to 7 µg/kg weekly with fixed dose rate gemcitabine without dose-limiting hypercalcemia. To the best of the authors' knowledge, the maximum tolerated dose has not been formally established to date. Preliminary clinical activity deserves further exploration., (© 2018 American Cancer Society.)

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1. Uridine uptake was inhibited by non-labeled GEM and also by S-(4-nitrobenzyl)-6-thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration-dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high- and low-affinity components with K m values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration-dependent manner by NBMPR and was sodium ion-independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low-affinity site. These results indicated that the high- and low-affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM-HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM-HAI., (Copyright © 2018 John Wiley & Sons, Ltd.)

This study investigated the effects of ingested food types on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir as a single-tablet regimen (STR) in Japanese HIV-negative healthy subjects. In this open-label, randomized, three-way crossover study, the pharmacokinetic profiles of elvitegravir, cobicistat, emtricitabine, and tenofovir were evaluated when administered with a standard breakfast, under fasting conditions, or with a nutritional protein-rich drink. All subjects (N = 11) received a single morning dose of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (150/150/200/300 mg). Administration under fasting conditions resulted in decreases in the mean AUCinf of elvitegravir and tenofovir by 50% and 28%, respectively, relative to administration with a standard breakfast, whereas the bioavailabilities of elvitegravir and tenofovir were comparable when administered with a standard breakfast or a nutritional protein-rich drink. Under fasting conditions, it appears that the bioavailabilities of elvitegravir and tenofovir were not equivalent to those when they were administered with either type of food, although they were bioequivalent to each other under fed conditions. Cobicistat and emtricitabine were bioequivalent under all conditions. These findings suggest that elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate should be administered with food, and that the bioavailability of elvitegravir and tenofovir is not affected by the type of meal ingested., (© 2014 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Mericitabine, the di-isobutyl ester prodrug of the cytidine nucleoside analog, is a potent and selective hepatitis C virus NS5B polymerase inhibitor. This thorough QT/QTc study evaluated the effect of mericitabine on cardiac repolarization in healthy subjects. This was a randomized, double-blind, placebo- and active-controlled, 4-way crossover study. A total of 60 subjects were enrolled and randomized to receive a single dose of mericitabine 1,500 mg, 9,000 mg, moxifloxacin 400 mg and placebo in randomly assigned treatment sequences, with at least 14 days between doses. The primary endpoint was the mean difference in baseline-adjusted QT interval using a study-specific correction method (QTcS) between mericitabine and placebo. The upper one-sided 95% confidence interval for the placebo-subtracted change from baseline in QTcS was <10 milliseconds and the mean difference from placebo was <5 milliseconds at all time points for both mericitabine doses. The positive control moxifloxacin caused a pronounced increase in QTcS that peaked 4 hours after oral administration. Furthermore, there was no trend of a concentration-dependent effect of mericitabine on QTcS. In conclusion, mericitabine does not have a clinically or statistically significant effect on cardiac repolarization in healthy subjects at single doses up to 9,000 mg., (© 2014, The American College of Clinical Pharmacology.)

The effect of food on rilpivirine/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (STR) was evaluated in healthy subjects. Subjects (N = 24) received rilpivirine/emtricitabine/tenofovir disoproxil fumarate (25/200/300 mg) under fasted or fed conditions (light [390 kcal, 12 g fat]; standard [540 kcal, 21 g fat]) followed by pharmacokinetic (PK) sampling. The 90% confidence interval (CI) of the geometric mean ratio for rilpivirine, emtricitabine, tenofovir exposure was estimated for fed versus fasted dosing and light versus standard meal, with equivalence boundaries of 80 - 125%. Safety was assessed throughout study. Twenty-three subjects completed the study; one discontinued due to protocol violation. Adverse events were mild to moderate. Emtricitabine PK was unaffected. Tenofovir AUCinf was 38% and 28% higher, respectively, with standard and light meal versus fasted. Rilpivirine AUCinf and Cmax were 16% and 26% higher with a standard, and 9% and 34% with a light meal, respectively, versus fasted. Compared to standard meal, the lower limit of rilpivirine AUClast and AUCinf when taken with the light meal were narrowly below the equivalence bounds (79.9 and 79.2, respectively), rilpivirine Cmax was narrowly above (129). Rilpivirine/emtricitabine/tenofovir disoproxil fumarate should be administered with food, which can be a standard or light meal., (© 2013, The American College of Clinical Pharmacology.)

Powerful array-based single-nucleotide polymorphism-typing platforms have recently heralded a new era in which genome-wide studies are conducted with increasing frequency. A genetic polymorphism associated with population pharmacokinetics (PK) is typically analyzed using nonlinear mixed-effect models (NLMM). Applying NLMM to large-scale data, such as those generated by genome-wide studies, raises several issues related to the assumption of random effects as follows: (i) computation time: it takes a long time to compute the marginal likelihood; (ii) convergence of iterative calculation: an adaptive Gauss-Hermite quadrature is generally used to estimate NLMM; however, iterative calculations may not converge in complex models; and (iii) random-effects misspecification leads to slightly inflated type-I error rates. As an alternative effective approach to resolving these issues, in this article, we propose a generalized estimating equation (GEE) approach for analyzing population PK data. In general, GEE analysis does not account for interindividual variability in PK parameters; therefore, the usual GEE estimators cannot be interpreted straightforwardly, and their validities have not been justified. Here, we propose valid inference methods for using GEE even under conditions of interindividual variability and provide theoretical justifications of the proposed GEE estimators for population PK data. In numerical evaluations by simulations, the proposed GEE approach exhibited high computational speed and stability relative to the NLMM approach. Furthermore, the NLMM analysis was sensitive to the misspecification of the random-effects distribution, and the proposed GEE inference is valid for any distributional form. We provided an illustration by using data from a genome-wide pharmacogenomic study of an anticancer drug., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objectives: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented., Methods: HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population., Results: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects., Conclusions: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients., (© 2013 British HIV Association.)

During pregnancy, the disposition of various drugs is altered due to changes in physiological condition, maternal gastrointestinal absorption, gastric secretion and motility. A fixed dose combination of antiretrovirals is commonly prescribed for the treatment of HIV infection. There is a need to understand the pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir in fixed dose combination during pregnancy. The pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir fixed dose combination was evaluated in timed pregnant and non-pregnant Sprague-Dawley rats at 30, 10, 15 mg/kg p.o., respectively. The plasma, placental tissue, amniotic fluid and fetal tissue concentrations were measured using high performance liquid chromatography combined with tandem mass spectrometric detector (LC-MS/MS). To summarize, the pharmacokinetic profile of efavirenz remained similar in the pregnant and non-pregnant rats. However, a considerable difference in the pharmacokinetics of emtricitabine and tenofovir was observed in pregnant and non-pregnant rats. Efavirenz and emtricitabine showed appreciable placental, amniotic fluid and fetal exposure compared with tenofovir. The present study suggests that a profound impact on antiretroviral pharmacokinetics was observed during pregnancy and there is a need to monitor the exposure levels of each drug when administered as a fixed dose combination during pregnancy. Further studies to explore the pharmacokinetic parameters of fixed dose antiretrovirals during the preclinical stage in a timed-pregnancy rat model are required. Such studies can help in the development of safe and effective medications with a reduced risk of perinatal transmission of HIV-1 infection., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objectives: The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum., Methods: The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6-12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography-mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC(0-24) ), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects., Results: Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1-8.9) vs. 9.7 (8.6-10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6-28.3) vs. 20.6 (18.4-23.2) L/h (P = 0.025); 24 hour post dose concentration (C(24) ): 0.058 (0.037-0.063) vs. 0.085 (0.070-0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0-1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects., Conclusions: While we found higher emtricitabine CL/F and lower C(24) and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations., (© 2011 British HIV Association.)

Objectives: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks., Methods: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis., Results: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks., Conclusions: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar., (2011 British HIV Association.)

The anticancer drug capecitabine and its metabolites [including the active metabolite 5-fluorouracil (5-FU)] display high pharmacokinetic inter-patient variability. Such variability, which may lead to treatment failure or toxicity, could need drug concentration measurement to individualize dosing regimen. However, usual assay methods are often long and fastidious. A simultaneous and cost-effective method was thus developed for the determination of the concentrations of these compounds in human plasma. Compounds were extracted via a classic liquid-liquid extraction. Chromatographic analysis was performed on a C18 reverse phase column with detection by atmosphere pressure chemical ionization LC-MS/MS. Our method allows a good chromatographic separation of the compounds and was fully validated following Food and Drug Administration (FDA) recommendations (good selectivity, no carry-over, linearity of the calibration curves without weighting, deviations from nominal concentrations of standard samples lower than 15%, intra- and inter-assay precision and accuracy lower than 15%). Recovery and stability were also acceptable following the FDA guidelines. A matrix effect impairing the determination of 5-FU was avoided by using a stable isotopic derivative of 5-FU as internal standard. Interestingly, this method allows detection of TetraHydroUridine, an inhibitor of ex vivo degradation of metabolites, which is essential for the stability, the adequate conditioning of blood samples and for good laboratory practice, essential in routine determination. This method seems usable to routinely determine concentrations of capecitabine and its metabolites in blood and may be helpful in further studies aiming at performing therapeutic drug monitoring., (Copyright 2010 John Wiley & Sons, Ltd.)

For the purpose of developing a longitudinal model to predict hand-and-foot syndrome (HFS) dynamics in patients receiving capecitabine, data from two large phase III studies were used. Of 595 patients in the capecitabine arms, 400 patients were randomly selected to build the model, and the other 195 were assigned for model validation. A score for risk of developing HFS was modeled using the proportional odds model, a sigmoidal maximum effect model driven by capecitabine accumulation as estimated through a kinetic-pharmacodynamic model and a Markov process. The lower the calculated creatinine clearance value at inclusion, the higher was the risk of HFS. Model validation was performed by visual and statistical predictive checks. The predictive dynamic model of HFS in patients receiving capecitabine allows the prediction of toxicity risk based on cumulative capecitabine dose and previous HFS grade. This dose-toxicity model will be useful in developing Bayesian individual treatment adaptations and may be of use in the clinic.

Background: Gemcitabine incorporation into DNA enhances cleavage complexes in vitro when combined with topoisomerase I inhibitors and demonstrates synergy in cancer cells when given with irinotecan. Topoisomerase I inhibitors require that topoisomerase I interacts with DNA to exert activity., Methods: Patients who had received previous anthracycline therapy or were not candidates for anthracycline therapy received gemcitabine at a dose of 1000 mg/m2 intravenously over 30 minutes followed by irinotecan at a dose of 100 mg/m2 over 90 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was improvement in response from that historically observed with gemcitabine (from 25% to 45%) as measured by Response Evaluation Criteria in Solid Tumors. Correlative studies included characterization of cellular levels and nuclear distribution of topoisomerase I and pharmacokinetic analysis of gemcitabine and irinotecan., Results: Forty-nine patients were assessed for response. The response rate was approximately 25% (all partial responses [PRs], 12 patients; 95% confidence interval [95% CI], 13-39). Six patients had stable disease (SD) for > or =6 months for a clinical benefit rate (PR + SD) of 39%. The median time to disease progression was 3.7 months (95% CI, 2.5 months-4.6 months), and median survival was 11.6 months (95% CI, 8.9 months-15 months). Toxicities included neutropenia, nausea, and vomiting. Seven of 9 tissue biopsies were assessable for topoisomerase I. Tumors with the 2 lowest nuclear to cytoplasmic ratios demonstrated no response to irinotecan., Conclusions: Gemcitabine and irinotecan are active in metastatic breast cancer, but response did not meet predetermined response parameters, and the null hypothesis was accepted. Topoisomerase I localization can be measured in metastatic breast cancer. Further validation is needed to determine whether this assay can predict response.

Background: : Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a 21-day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of

The anticancer agent indisulam was evaluated in a dose-escalation study in combination with capecitabine. Severe myelotoxicity was observed after multiple treatment cycles. We hypothesized that capecitabine inhibits the synthesis of CYP2C9, which metabolizes indisulam. The objectives were to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the combination treatment and to estimate the impact of a drug-drug interaction on the safety of various dose levels. NONMEM was used to develop a PK/PD model, including the impact of capecitabine coadministration on indisulam pharmacokinetics. A simulation study was performed to evaluate the risk of dose-limiting neutropenia. A time-dependent pharmacokinetic drug-drug interaction resulted in increased exposure to indisulam and in increased myelotoxicity. The risk of dose-limiting neutropenia increased with treatment duration and with dose. The excessive myelosuppression after multiple cycles may be explained by a pharmacokinetic interaction between indisulam and capecitabine. The combination of 550 mg/m(2) indisulam and 1,250 mg/m(2) capecitabine twice daily was considered safe.

Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC) is a pyrimidine antimetabolite employed against several human malignancies. It undergoes intracellular activation to the pharmacologically active triphosphate form (dFdCTP) and metabolic inactivation to the metabolite 2',2'-difluorodeoxyuridine (dFdU). In order to investigate the human plasma pharmacokinetics of dFdC and dFdU, we developed and validated an HPLC-MS/MS method, adding 2'-deoxycytidine as internal standard and simply precipitating the protein with acetonitrile. The method requires a small sample (125 microl), and it is rapid and selective, allowing good resolution of peaks from the plasma matrix in only 7 min. It is sensitive, precise and accurate, with overall precision, expressed as CV%, always less than 10.0% for both analytes and high recovery: > or = 80%. The limits of detection for dFdC and dFdU were 0.1 and 1.1 ng/ml, but considering the high concentrations in the plasma of patients investigated, we set the limit of quantitation at 20 ng/ml (0.08 microM) for dFdC and 250 ng/ml for dFdU, and validated the assay up to the dFdC concentration of 6.0 microg/ml (22.8 microM). The method was successfully used to study the drug pharmacokinetics in patients with advanced non-small-cell lung cancer in a phase II trial with gemcitabine administered as a fixed dose-rate infusion., ((c) 2008 John Wiley & Sons, Ltd.)

Nuclear magnetic resonance spectroscopy of fluorine-19 ((19)F NMR) has proven useful for evaluating kinetics of fluorinated chemotherapy drugs in tumors in vivo. This work investigated how three perfusion-enhancing vascular modifiers (BQ123, thalidomide, and Botulinum neurotoxin type A [BoNT-A]) would affect the chemotherapeutic efficacy of gemcitabine, a fluorinated drug widely used in human cancer treatment. Murine tumor growth experiments demonstrated that only BoNT-A showed a strong trend to enhance tumor growth inhibition by gemcitabine (1.7 days growth delay, P = 0.052, Student t-test). In accord with these results, (19)F NMR experiments showed that only BoNT-A increased significantly the uptake of gemcitabine in tumors (50% increase, P = 0.0008, Student t-test). Further experiments on gemcitabine kinetics (NMR vs time) and distribution ((19)F MRI) confirmed the uptake-enhancing properties of BoNT-A. The results of this study demonstrate that (19)F NMR can monitor modulation of the pharmacokinetics of fluorinated chemotherapy drugs in tumors. The results also show that (19)F NMR data can give a strong indication of the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy in murine tumors. (19)F NMR is a promising tool for preclinical evaluation of such vascular modifiers and may ultimately be used in the clinic to monitor how these modifiers affect chemotherapy., (2007 Wiley-Liss, Inc)

Emtricitabine is a potent nucleoside reverse transcriptase inhibitor approved as a once-daily drug in combination with other antiretroviral agents for the treatment of HIV infection. Several phase I studies were conducted in healthy volunteers over the course of clinical development to evaluate whether pharmacokinetic drug-drug interactions exist between emtricitabine and other nucleoside antivirals that are extensively eliminated by renal excretion. Potential interactions with stavudine and famciclovir were evaluated in single-dose studies, whereas interactions with zidovudine and its major metabolite, zidovudine glucuronide, were evaluated in a multiple-dose study. Plasma pharmacokinetic profiles and, in some studies, urinary excretion data were evaluated when each drug was administered alone and in combination with emtricitabine. Safety and plasma pharmacokinetic profiles of each drug administered alone or with emtricitabine were consistent with historical data. Statistical analyses indicated that there were no significant interactions between emtricitabine and these 3 nucleoside antivirals.

The approved antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, were considered good candidates for a fixed-dose combination product that could be administered as a single pill once daily (qd), thereby simplifying existing treatment regimens and promoting patient adherence. As both drugs are extensively renally eliminated, a randomized, 3-way crossover study was conducted in 19 healthy volunteers to formally evaluate the potential pharmacokinetic interaction when the drugs are administered alone and together (ie, 200 mg emtricitabine qd for 7 days, 300 mg tenofovir disoproxil fumarate qd for 7 days, and 200 mg emtricitabine plus 300 mg tenofovir disoproxil fumarate qd for 7 days) with no washout between treatments. Steady-state pharmacokinetic parameters (AUC(tau), C(max), and C(min)) of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) in combination were essentially equivalent versus each drug alone, providing a pharmacokinetic rationale for combining these products in emtricitabine/tenofovir disoproxil fumarate fixed-dose tablets.

Gemcitabine triphosphate (dFdCTP) is a highly active metabolite of gemcitabine. It is formed intra-cellularly via the phosphorylation of gemcitabine by deoxycytidine kinase. The monitoring of dFdCTP in human peripheral blood mononuclear cells (PBMCs), in addition to plasma concentrations of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine, is considered very useful in determining pharmacokinetic-pharmacodynamic relationships. We describe a novel sensitive assay for the quantification of dFdCTP in human PBMCs. The method is based on weak anion-exchange liquid chromatography and detection with tandem mass spectrometry (LC-MS/MS). The assay has been validated from 1 ng/ml (lower limit of quantification, LLOQ) to 25 ng/ml (upper limit of quantification, ULOQ) using 180 microl aliquots of PBMC extracts containing approximately 0.648 mg protein or 3.8 x 10(6) lysed PBMCs. The LLOQ is equivalent to 94 fmol/10(6) cells (1 ng/ml = 0.18 ng/180 microl or 0.18 ng/0.648 mg protein = 0.047 ng/10(6) cells or 94 fmol/10(6) cells). This highly sensitive assay is capable of quantifying about 200-fold lower concentrations of dFdCTP in human PBMCs than currently available methods.

Objective: This study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once-daily combination., Methods: Nine antiretroviral-naïve HIV-infected adults who received FTC [200 mg once a day (q.d.)], ddI (400 mg q.d. if > or =60 kg; 250 mg q.d. if <60 kg) and EFV (600 mg q.d.) were studied. The following pharmacokinetic (PK) parameters were determined over 24 h at steady-state after 4 weeks of treatment: area under the plasma concentration vs. time curve (AUC(0-24 h)), maximum (Cmax) and minimum (Cmin) plasma concentrations, time to reach Cmax (Tmax), and the elimination half-life (t(1/2)). EFV plasma concentrations were also measured during follow-up., Results: Median PK parameters for FTC, ddI and EFV, respectively, were as follows. AUC(0-24 h): 7.2, 7.0 and 36.4 h x mg/L; Cmax: 1.8, 2.6 and 2.5 mg/L; Cmin: 0.04, <0.01 and 1.0 mg/L; Tmax: 1.8, 1.1 and 2.5 h; t(1/2): 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10-13 h postdosing were higher during follow-up than during the PK study (2.57 vs. 1.19 mg/L, P<0.01)., Conclusion: The simultaneous administration of FTC, ddI and EFV did not affect the PK parameters of FTC when compared to historical controls. EFV Cmax and Cmin were lower than expected, but the data may have been slightly underestimated in this study. High ddI AUC and Cmax were measured in these patients, and further studies are warranted to confirm this finding.

The objective of this study was to evaluate the effect of food on the pharmacokinetics of racemic dOTC, a nucleoside analogue reverse transcriptase inhibitor, in adult male volunteers. Twelve healthy adult male subjects were enrolled in a randomized, open-label, single-dose crossover study. All were nonsmoking, within 15% of ideal body weight, and between 18 and 50 years of age. Subjects received single oral doses of 800mg racemic dOTC, in random order, either fed or fasted. The meal given to fed subjects was the standard Food and Drug Administration high-fat breakfast, and all subjects completed both study periods. Sixteen plasma samples for pharmacokinetic assessments were collected for 72 hours following dosing and assayed for (-) and (+) dOTC concentrations. Area under the plasma concentration-time curve (AUC), maximum observed plasma concentration (Cmax), and time to maximum concentration (tm) were determined for each enantiomer by standard noncompartmental techniques. Statistical hypothesis testing was by Wilcoxon signed rank, and the two one-sided tests procedure was used to determine bioequivalence between thefed and fasted study periods. The only effect of coadministration of racemic dOTC with food was a delay in time to peak concentration (t(max) of between 0.6 and 0.7 hours for both (-) and (+) dOTC stereoisomers (p < or =0.02). Neither AUC (p > or = 0.10) nor Cmax (p > or = 0.35) differed significantly between the fed and fasted study periods for either (-) or (+) dOTC. Both AUC and Cmax were equivalent between the fed and fasted study periods. It was concluded that there is no clinically significant effect of a high-fat meal on the pharmacokinetics of either (-) or (+) dOTC when administered orally as a racemic mixture.

The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated., (Copyright 2001 John Wiley & Sons, Ltd.)