Absorption, distribution, metabolism and excretion of molidustat in healthy participants.

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat-related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M-1, produced by N-glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration-time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7-34.5 L/h and volume of distribution at steady state was 39.3-50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.

Influence of Sustained Low-Efficiency Dialysis Treatment on Isavuconazole Plasma Levels in Critically Ill Patients.

Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 µg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.

The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer.

BACKGROUND: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. METHODS: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. RESULTS: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. CONCLUSIONS: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

Deferasirox-Iron Complex Formation Ratio as an Indicator of Long-term Chelation Efficacy in ß-Thalassemia Major.

BACKGROUND: ß-Thalassemia major patients with higher total drug levels [deferasirox (DEFR) plus its iron complex] do not yield better serum ferritin (SF) control. This study aimed to determine the concentrations of DEFR and its iron complex (Fe-[DEFR]2) in thalassemia patients to predict the chelation efficacy in terms of SF and cardiac T2* values. METHODS: Patients' steady-state drug levels at trough (Ctrough) and 2 hours postdose (C2h) were determined. Because iron deposition may cause changes in the hepatic metabolism of amino acids, the concentrations of 40 amino acids in plasma were also assayed at 2 hours postdose. RESULTS: A total of 28 patients either dosing daily or twice daily were recruited. After a 1-month DEFR maintenance therapy, 38.8% and 30% of patients from groups of once-daily and twice-daily, respectively, had a plasma DEFR-iron complex formation ratio higher than 0.05 [High Chelation Ratio, (HCR)]. After a 6-month follow-up, those patients who had a HCR (n = 10) at C2h showed more favorable median changes in SF and cardiac T2* values (-388.0, +10.1) than those with a low DEFR-iron complex formation ratio (Low Chelation Ratio; n = 18; +10.5; +4.5) compared with the baseline. The levels of plasma L-arginine, L-alanine, L-glycine, L-norleucine, and L-serine were significantly lower in patients with the low Chelation Ratio condition than the levels in HCR patients. CONCLUSIONS: This therapeutic drug monitoring study revealed that a DEFR-iron complex formation ratio at C2h might be an applicable indicator of the efficacy of long-term DEFR iron chelation therapy. A better iron-control response to DEFR was observed in the patients with HCRs. The trends for the ratio might have value in dose-setting and need to be validated in a larger cohort.

Role of pharmacogenetics on deferasirox AUC and efficacy.

AIM: We evaluated deferasirox pharmacokinetic according to SNPs in genes involved in its metabolism and elimination. Moreover, we defined a plasma area under the curve cut-off value predicting therapy response. PATIENTS & METHODS: Allelic discrimination was performed by real-time PCR. Drug plasma concentrations were measured by a high performance liquid chromatography system coupled with an ultraviolet method. RESULTS: Pharmacokinetic parameters were significantly influenced by UGT1A1 rs887829C>T, UGT1A3 rs1983023C>T and rs3806596A>G SNPs. Area under the curve cut-off values of 360 µg/ml/h for efficacy were here defined and 250 µg/ml/h for nonresponse was reported. UGT1A3 rs3806596GG and ABCG2 rs13120400CC genotypes were factors able to predict efficacy, whereas UGT1A3 rs3806596GG was a nonresponse predictor. CONCLUSION: These data show how screening patient's genetic profile may help clinicians to optimize iron chelation therapy with deferasirox.

Simultaneous Determination of Plasma Deferasirox and Deferasirox-Iron Complex Using an HPLC-UV System and Pharmacokinetics of Deferasirox in Patients With ß-Thalassemia Major: Once-daily Versus Twice-daily Administration.

PURPOSE: Deferasirox (DEFR), when administered BID, improves iron overload and decreases DEFR-related adverse effects in patients with ß-thalassemia major. However, the pharmacokinetic (PK) disposition of DEFR and the iron-DEFR complex (Fe-[DEFR]2) in this dosing strategy is unclear. METHODS: Chromatographic analysis was performed using a solvent delivery system coupled to an HPLC-UV detector to determine the steady-state concentrations of DEFR (CDEFR) and Fe-(DEFR)2 (CFe-[DEFR]2) in ß-thalassemia major patients (n = 8) following either once-daily or BID dosing, during which the PK parameters of the 2 dosing schedules were compared. FINDINGS: An HPLC-UV system for the analysis of blood samples following solid-phase extraction was validated. Patients who received 40 mg/kg of DEFR had higher mean CDEFR and CFe-[DEFR]2 values at all sampling times. However, concentrations of iron-DEFR complex were similar in patients who received 30 or 40 mg/kg of DEFR in the once-daily group at the 6- to 24-hour sampling times. There was no significant difference in any of the PK parameters; however, DEFR administration BID increased the mean trough levels of DEFR (183.8 [157.5] µmol/L) compared with once daily (87.7 [56.8] µmol/L), whereas all the patients had increased peak levels per individual DEFR dose when they were switched from once daily to BID (139.0 [59.8] µmol/L vs 289.2 [145.8] µmol/L, respectively). IMPLICATIONS: Splitting the dose increased the peak levels of DEFR per unit dose in all patients and tends to increase drug exposures, but there were no significant differences in DEFR PK parameter estimates. Switching from once daily to BID may be considered for patients with an inadequate response to chelation therapy to achieve optimal drug levels. Further research is needed with a larger sample size to determine the clinical importance of the significant results due to the interindividual variability of DEFR.

Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole.

PURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.

Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.

STUDY QUESTION: Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile? SUMMARY ANSWER: The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys. WHAT IS KNOWN ALREADY: ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials. STUDY DESIGN, SIZE, DURATION: The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days). MAIN RESULTS AND THE ROLE OF CHANCE: ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 µg/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E2) levels by ∼30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts. LIMITATIONS, REASONS FOR CAUTION: The study was limited to three dose groups in which only the highest dose decreased the E2 level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys. WIDER IMPLICATIONS OF THE FINDINGS: The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human.

Determination of voriconazole serum concentration by bioassay, a valid method for therapeutic drug monitoring for clinical laboratories.

We describe here a simple, fast, and reliable bioassay method for therapeutic drug monitoring of voriconazole. Fifty-eight clinical and external quality control samples were evaluated with this microbiological assay, and results were compared with those obtained with a previously validated chromatographic method. A good correlation between both assays was observed. This particular microbiological method was demonstrated to be simple and offers enough precision and accuracy to perform voriconazole therapeutic drug monitoring in laboratories without specialized equipment.

Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.

STUDY OBJECTIVE: To evaluate the relationship between voriconazole dose and corresponding serum concentrations in obese and overweight immunocompromised patients. DESIGN: Retrospective medical record review. SETTING: National Cancer Institute-designated comprehensive cancer center. PATIENTS: A total of 92 patients with hematologic malignancies and/or hematopoietic stem cell transplants who received voriconazole and had reported steady-state serum concentrations (peak, random, or trough) during 2005-2010; 124 serum concentrations were available for analysis. MEASUREMENTS AND MAIN RESULTS: Data on patient demographics, voriconazole concentrations, and other clinical and safety data were collected. Patients were stratified based on body mass index (BMI). Patients with higher BMIs tended to have significantly higher median random voriconazole concentrations with intravenous administration (6.4 mg/L for BMI ≥ 25 kg/m(2) vs 2.8 mg/L for BMI < 25 kg/m(2), p=0.04). This trend was more notable with the intravenous than the oral formulations. With the oral formulation, patients with a BMI of 25 kg/m(2) or greater had a median random concentration of 2.8 mg/L compared with 2.0 mg/L in patients with a BMI less than 25 kg/m(2) (p=0.18). Patients with a BMI of 25 kg/m(2) or greater also had a higher median daily voriconazole dose (640 vs 400 mg, p<0.001). No significant differences were noted in factors that would affect oral absorption of voriconazole (e.g., graft-versus-host disease) among BMI groups. When comparing all voriconazole concentrations, higher concentrations were associated with a greater percentage of patients who had alanine aminotransferase levels of more than 3 times the upper limit of normal. Patients with voriconazole random concentrations of 2 mg/L or greater had higher response rates (50%) than patients with concentrations lower than 2 mg/L (33%). CONCLUSION: Standard voriconazole dosing using actual body weight in obese and overweight patients resulted in higher associated serum concentrations. Dosing using adjusted body weight may be necessary in this population in order to achieve optimal concentrations while preventing the potential for increased toxicity.

Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection.

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.

Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C(avg)) and clinical response and between the free C(avg)/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P = 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P = 0.014), and pathogen (yeast/mold, P < 0.001). The C(avg) for 72% of the patients was 0.5 to 5.0 µg/ml, with the maximum response rate (74%) at 3.0 to 4.0 µg/ml. The C(avg) showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C(avg) < 0.5 µg/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C(avg) ≥ 5.0 µg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C(avg)/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C(avg). Patients with higher free C(avg)/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.

Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring.

Very low voriconazole concentrations are commonly observed during therapeutic drug monitoring. Possible mechanisms include inappropriate dose selection, rapid metabolism (as a result of genetic polymorphisms or enzyme induction), and also nonadherence. We aimed to develop a method to distinguish between rapid metabolism of and nonadherence to voriconazole by quantification of voriconazole metabolites. In addition, the relevance of common genetic polymorphisms of CYP2C19 was assessed. In a retrospective study, samples with voriconazole concentrations 0.2 µg/mL or less in routine therapeutic drug monitoring (as quantified by high-performance liquid chromatography) were evaluated. Voriconazole and its N-oxide metabolite were quantified in residual blood using a highly sensitive liquid chromatography-tandem mass spectroscopy method (lower limit of quantitation = 0.03 µg/mL). Genetic polymorphisms of CYP2C19 were determined by real-time polymerase chain reaction using the hybridization probe format and the polymerase chain reaction-random fragment length polymorphism format. A total of 747 routine therapeutic drug monitoring plasma/blood samples of 335 patients treated with systemic voriconazole were analyzed and in 18.7% of all samples, voriconazole concentrations 0.2 µg/mL or less were found. In 32 samples (30 patients) with adequate dosage and timing of blood withdrawal, nonadherence was strongly suspected in seven patients because voriconazole-N-oxide concentrations were below 0.03 µg/mL, which was not observed in a reference group of 51 healthy volunteers with controlled drug intake. In 10 patients, of whom EDTA blood was available, the ultrarapid metabolizer genotype (CYP2C19*1\*17, CYP2C19*17\*17) was found in 80% and its prevalence was significantly higher as compared to a reference group (P = 0.02). In conclusion, quantification of voriconazole-N-oxide allowed for detection of suspected nonadherence in one of four patients with very low voriconazole concentrations. In the remaining patients, ultrarapid metabolism resulting from the CYP2C19*17 polymorphism appears to play a major role. Thus, in the case of voriconazole therapy failure, both nonadherence and genetic factors have to be considered.

Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans: physiologically based pharmacokinetic model versus traditional one-compartment model.

The objective of this study was to assess the physiologically based pharmacokinetic (PBPK) model for predicting plasma concentration-time profiles of orally available cMet kinase inhibitors, (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) and 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (PF04217903), in humans. The prediction accuracy of pharmacokinetics (PK) by PBPK modeling was compared with that of a traditional one-compartment PK model based on allometric scaling. The predicted clearance values from allometric scaling with the correction for the interspecies differences in protein binding were used as a representative comparison, which showed more accurate PK prediction in humans than the other methods. Overall PBPK modeling provided better prediction of the area under the plasma concentration-time curves for both PF02341066 (1.2-fold error) and PF04217903 (1.3-fold error) compared with the one-compartment PK model (1.8- and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t(1/2)): the observed and predicted t(1/2) values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t(1/2) values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.

Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.

Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58-45.2 and 0.635-97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50-2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to "individualize" therapy with this drug.

Lack of effect of Ginkgo biloba on voriconazole pharmacokinetics in Chinese volunteers identified as CYP2C19 poor and extensive metabolizers.

BACKGROUND: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. OBJECTIVE: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive or poor metabolizers. METHODS: Fourteen healthy, nonsmoking volunteers-7 CYP2C19 extensive metabolizers (2C19(*)1/2C19(*)1) and 7 poor metabolizers (2C19(*)2/2C19(*)2)-were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography-electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. RESULTS: For extensive metabolizers, the median value for voriconazole area under the plasma concentration-time curve from zero to infinity (AUC(0-)(infinity)) was 5.17 microg.h/mL after administration of voriconazole alone and 4.28 microg.h/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC(0-24), time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. CONCLUSIONS: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers.

A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost). In part 3, an SD of posaconazole (400 mg) was administered while the subjects were fasting and before, during, and after a high-fat meal. In part 4, an SD of posaconazole (400 mg) and the nutritional supplement were administered alone, with metoclopramide, and with loperamide. Compared to the results obtained with posaconazole alone, administration with an acidic beverage increased the posaconazole maximum concentration in plasma (C(max)) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazole C(max) and AUC by 46% and 32%, respectively. Compared to the results obtained with posaconazole alone, posaconazole at 400 mg or at 200 mg plus the nutritional supplement increased the posaconazole C(max) and AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased the C(max) and the AUC by 96% and 111%, respectively, while administration during and after the meal increased the C(max) and the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased the C(max) and the AUC by 21% and 19%, respectively. Strategies to maximize posaconazole exposure in patients with absorption difficulties include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses and the avoidance of proton pump inhibitors.

High performance liquid chromatographic determination of a new antifungal compound, ADKZ in rat plasma.

A high performance liquid chromatography (HPLC) method was developed and validated for the determination of ADKZ (1-(1H-1,2,4-triazole)-2-(2,4-diflurophenyl) -3-[N-methyl-N-(4-iodo-benzyl)amino]-2-propanol) in rat plasma. The compound was extracted from plasma samples by liquid-liquid extraction, and an isomeric compound of ADKZ (1-(1H-1,2,4-triazole)-2-(2,4-diflurophenyl)-3-[N-methyl-N -(3-iodo-benzyl)amino]-2-propanol) was used as the internal standard (IS), which were analyzed on a reversed-phase C18 column (5 microm, 200 mm x 4.6 mm i.d.). The extracted plasma samples were eluted with acetonitrile-0.018 M triethylamine solution adjusted to pH 3.2 with phosphoric acid (35:65, v/v). The effluent was monitored by a UV detector at 230 nm. The retention time of ADKZ was 7.1 min and IS 8.2 min. The calibration curves were linear in the concentration range of 0.02-2.00 microg/ml with the correlation coefficients greater than 0.999. The quantification limit of ADKZ in rat plasma was 0.02 microg/ml. Intra- and inter-day precision ranged from 2.6 to 7.9% and 3.1 to 9.6%, respectively. The extraction recovery from plasma was no less than 80%. No endogenous interferences were observed with either ADKZ or IS. The method has been successfully used to support the pre-clinical pharmacokinetic studies of ADKZ in rats.