Difference In AUC Research Articles

Pharmacokinetic/pharmacodynamic comparison between generic and brand-name levofloxacin based on Monte Carlo simulation

The generic drugs are widely used due to its substantially low price. However, some generic drugs showed lower efficiency in terms of quality and clinical efficacy compared with brand-name drugs, especially for antimicrobial drugs. Levofloxacin is a fluoroquinolone antimicrobial drug with excellent antimicrobial activity and wide antimicrobial spectrum, while it is susceptible to drug resistance. Our study aims to evaluate the bioequivalence of generic and brand-name levofloxacin. The pharmacokinetic (PK) parameters (Cmax, AUC0∼24, Tmax and t1/2), pharmacodynamic (PD) parameters (in vitro antibacterial activity and the inhibition of resistant mutation), and PK/PD analysis (the probability of target attainment, PTA; the cumulative fraction of response, CFR) calculated by Monte Carlo simulation (MCS) were investigated. Our results demonstrated that compared with the generics, the brand-name levofloxacin not only had higher drug content, but also showed higher antimicrobial susceptibility, higher resistance to mutation ability and higher percentage of each dosage interval that plasma concentration of antimicrobial agents exceeded the MPC90 (mutant prevention concentrations to prevent the mutation of 90% strains) against various clinical isolates. Although the PK results showed the differences in AUC0∼24 between brand-name levofloxacin and generics were not statistically significant (p > 0.05, F-test), the MCS results showed CFR of PK/PD of brand-name drugs were higher than generics. Our results indicated that PK or PD equivalence did not imply the therapeutic equivalence, thus, we suggest to include PK/PD analysis in bioequivalence evaluation system, which is beneficial to the prediction of clinical out come with high application value.

Influence of esomeprazole on the bioavailability of afatinib: A pharmacokinetic cross-over study in patients with non-small cell lung cancer

Afatinib is an oral small-molecule kinase inhibitor (SMKI) approved for treatment of metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) driver mutation. Although oral administration is convenient, most SMKIs experience pH-dependent solubility. A drug-drug interaction between afatinib and proton-pump inhibitors (PPIs) has, however, never been studied in humans. Hence, we performed a randomized, three-period cross-over study. Afatinib (30 mg or 40 mg) was administered without PPI (period A), concomitantly with esomeprazole (period B) and three hours after esomeprazole intake (period C). Primary objective was the area under the curve (AUC0–24 h) comparing period A to period B and period A to period C. Secondary objectives were other pharmacokinetic parameters and toxicity. Linear mixed effect modelling was performed for differences in AUC0–24 h and Cmax between periods A and B and periods A and C. In 18 evaluable NSCLC patients, concomitant use of 40 mg esomeprazole decreased the steady-state afatinib AUC0–24 h with 10.2% (95% CI −29.2 to +14.0%; p = 0.564) compared to afatinib administration without PPI. Esomeprazole intake three hours prior to afatinib did not significantly influence afatinib AUC0–24 h (−0.6%; 95% CI −14.9 to +16.1%; p = 1.0). No differences in toxicity were observed. To conclude, esomeprazole did not change the exposure to afatinib in patients with NSCLC. Since there is no clinically relevant drug-drug interaction, esomeprazole can safely be co-administered with afatinib. This is important for clinical practice, because other EGFR-SMKIs (e.g. erlotinib and gefitinib) do experience clinically relevant drug-drug interactions with acid-suppressive agents.

Impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of lenvatinib in patients with hepatocellular carcinoma

This prospective study examined the impact of genetic polymorphisms on the pharmacokinetics and clinical efficacy and safety of lenvatinib, a substrate of ATP-binding transporters, in a cohort of 48 Japanese patients with hepatocellular carcinoma (HCC). Pharmacokinetic studies were performed at the start of lenvatinib therapy (day 1) and on day 15. The coefficients of variation in AUC0–24h of lenvatinib on days 1 and 15 were 44.0% and 52.4%, respectively. Although the ABCB1 3435C > A, 1236C > T, and 2677G>T/A polymorphisms did not influence pharmacokinetic parameters, the AUC0–24h values on days 1 and 15 of the ABCG2 C/A or A/A group were approximately 1.1-fold and 1.4-fold that in the ABCG2 C/C group (P = 0.164 and 0.024). There were no significant differences in AUC0–24h on days 1 and 15 between the responders (complete or partial response) and non-responders (stable or progressive disease). The AUC0–24h on day 15 in those developing anorexia of any grade was significantly higher than that without such development (P = 0.017). In multivariate analysis, ABCG2 421C > A C/A or A/A was significantly associated with the development of anorexia (odds ratio 9.009, P = 0.009). ABCG2 421C > A polymorphism could affect exposure to lenvatinib and the development of anorexia.

Comparative pharmacokinetics of osmotic-controlled and immediate-release Eperisone tablet formulation in healthy human subjects using a sensitive plasma LC-ESI-MS/MS method

To evaluate and compare the pharmacokinetic (PK) characteristics of a newly developed oral osmotically controlled drug delivery system of Eperisone 150 mg tablets with Eperisone immediate release (IR) marketed tablet brand as a reference formulation. It was a single dose, two treatment, two sequence, randomized, crossover study, involving 12 healthy human subjects. A modified, sensitive LC-ESI-MS/MS method was developed and validated as per FDA guidelines for estimation of Eperisone in plasma using a simple extraction and quick protein precipitation method. Non-compartmental pharmacokinetic model was used for PK analysis. Results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with 90% CI limit of 0.8–1.25. The bio-analytical method used for estimating drug plasma concentration was found to be simple, selective, linear, accurate and precise with 0.01 ng/ml as limit of detection. The comparative PK analysis revealed an insignificant difference in AUC0-∞, AUC0-t, Vz/F, Cl/F and t1/2λz, whereas a significant difference in Cmax, Tmax and MTTs were found. The relative bioavailability of Eperisone osmotic tablet was 109.7%. The osmotic controlled release drug formulation was found to release Eperisone for an extended period with less inter individual fluctuation in pharmacokinetic variables.

Influence of ABCB1 polymorphisms on the pharmacokinetics and toxicity of lenalidomide in patients with multiple myeloma.

Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration-time curve (AUC0-24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0-24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0-24 in 1236C>T and 2677G>A/T polymorphisms. AUC0-24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21)(median 6324.6ngh/mL vs. 2857.4ngh/mL, p = 0.028). The AUC0-24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0-24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.

Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

ABSTRACTThere are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC0–28) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults (n = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC0–28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0–28, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml (P < 0.001). No significant differences in AUC0–28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC0–0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC0–0.75h values were evaluated versus differences in AUC0–1h and in AUC0–2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC0–0.75h, mean AUC0–1h, and mean AUC0–2h values were estimated using the lowest dose or the formulation with the lower AUC0–0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC0–0.75h ratios correlated significantly with log-transformed mean plasma AUC0–1h ratios. Based on this correlation, BioGIT AUC0–0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC0–1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.

Effects of hydrochlorothiazide and amlodipine on single oral dose pharmacokinetics of valsartan in healthy Korean subjects: Population model-based approach

Fixed dose combination (FDC) of valsartan (VAL) and hydrochlorothiazide (HCT) or VAL and amlodipine (AML) has been available in many countries for the treatment of hypertension. Due to drug-drug interaction potentials, in the current study we aimed to evaluate potent effects of HCT and AML on pharmacokinetics (PKs) of VAL when they are orally co-administered as FDC (VAL/HCT at 80/12.5 mg or 160/12.5 mg; and VAL/AML at 160/5 mg or 160/10 mg) products in healthy Korean subjects. Population pharmacokinetic (PK) modeling and analysis were performed by the nonlinear mixed-effects modeling software. PKs of VAL was described by two-compartment disposition model, first-order elimination, four-sequential first-order absorption model, correlation between apparent clearances and volumes of distribution, and lag time. For all FDCs, there were no statistically significant differences in both maximum concentration and areas under the concentration-time curves (AUCs) of VAL in comparison to those when administered VAL alone, except the combination of VAL/AML at 160/10 mg, where AUC0–∞ increased by 11.8% in mean and 6.86% in median. In addition, there was an increasing trend in time to reach peak (Tmax) of VAL in FDCs, where it was increased by 0.22–0.34 h in mean and 0.40–0.44 h in median, except the combination of VAL/HCT at 160/12.5 mg. However, these differences in AUC0–∞ and Tmax might not be considered as clinically important. In conclusion, HCT or AML has no potent effect on PKs of VAL when they are co-administered as FDC products. No dose adjustment for VAL is recommended when co-administered with HCT or AML.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. Randomized prospective crossover study. 50 African American maintenance kidney recipients on stable IR-Tac dosing. Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. Registered at ClinicalTrials.gov, with study number NCT01962922.

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m2 ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUCN (where AUC is area under the curve), CmaxN , and Tmax . Comparisons within each group revealed significant differences in AUC0-∞ and Tmax in the 5 mg/ml group. Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index

ObjectiveThis study compares the pharmacokinetics (PK) of levonorgestrel (LNG) emergency contraceptive (EC) and ulipristal acetate (UPA)-EC between normal-body mass index (BMI) and obese-BMI women. Study designThis prospective, randomized crossover study evaluates the PK of women after single doses of LNG-EC (1.5mg) and UPA-EC (30mg). Study procedures took place during clinical research unit admissions, where participants received a standardized meal and each study drug, in random order, during two separate 24-h admissions. Study staff collected 14 blood specimens (0, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 and 48h). We evaluated serum concentrations of LNG and UPA using liquid chromatography–tandem mass spectroscopy and estimated the PK parameters of both drugs using noncompartmental analysis. The main outcome of this study was a comparison of between-group differences in AUC0–24. ResultsThirty-two women completed the study (16 in each group). Among normal-BMI and obese-BMI participants, the mean BMIs were 22.0 (range 18.8–24.6) and 34.3 (range 30.6–39.9), respectively. After LNG-EC, mean AUC0–24 and maximum concentration (Cmax) were 50% lower among obese-BMI women than among normal-BMI women (AUC0–24 100.8 vs. 208.5ng*h/mL, IQRobese-BMI 35.8, IQRnormal-BMI 74.2, p≤.01; Cmax 10.8 vs. 18.2ng/mL, p=.01). After UPA-EC, AUC0–24 and Cmax were similar between obese-BMI and normal-BMI women (AUC0–24 362.5 vs. 293.5ng*h/mL, IQRobese-BMI 263.2, IQRnormal-BMI 112.5, p=.15; Cmax 95.6 vs. 89.3ng/mL, p=.70). ConclusionAfter a single dose of EC, obese-BMI women are exposed to lower concentrations of LNG and similar concentrations of UPA, when compared to normal-BMI women. ImplicationsDifferences in LNG-EC PK by BMI group may underlie and account for the lower LNG-EC efficacy reported among obese-BMI women, but modest differences in UPA-EC PK by BMI group provide less support for variable efficacy. A pharmacodynamic study may be able to clarify whether these PK differences account for observed differences in LNG-EC and UPA-EC efficacy.

A crossover pharmacokinetic study of misoprostol by the oral, sublingual and buccal routes

Objectives: The aim of the study was to compare the pharmacokinetic parameters of 800 μg oral, sublingual and buccal misoprostol in healthy non-pregnant women. Methods: This was an open-label, randomised study with a three-way crossover design. Eighteen participants were randomly assigned to treatment sequences of 800 μg oral, sublingual and buccal misoprostol administered under fasting conditions, with a 7-day washout period. Ten participants completed all routes. The primary pharmacokinetic parameters measured were the area under the plasma misoprostol acid concentration–time curve (AUC) from dosing to last quantifiable concentration (AUC0–t), the AUC from 0 to infinity (AUC0–∞) and the maximum plasma concentration (Cmax). Secondary parameters included the plasma elimination rate constant (ke), the half-life and the mean residence time (MRT). Results: There were statistically significant differences in AUC0–∞, AUC0–t and Cmax at the p < 0.05 level for the three routes of administration. The sublingual route achieved the highest bioavailability, and the buccal route achieved the lowest peak concentration. The oral and buccal routes had a similar AUC0–∞ and the buccal route had the highest MRT and ke. There were no differences in half-lives, and no serious adverse events were reported. Conclusions: This study shows variability in Cmax and AUC by three by-mouth routes of misoprostol administration. The dose in this study was 800 μg, which is among the highest doses seen in current guidelines. These data contribute to the understanding of efficacy and safety of different routes and could provide a basis for deciding whether certain routes are preferable for particular indications.

Bioequivalence evaluation of pioglitazone orally disintegrating tablet formulation

SUMMARY Three studies were performed in healthy Japanese men to compare the bioavailability of an orally disintegrating tablet formulation of pioglitazone (pioglitazone OD tablet) with pioglitazone commercial tablets, and to determine the extent of oral mucosal absorption. In two bioequivalence studies (both n = 64), pioglitazone OD tablets 30 mg were administered without (Study 1) or with water (Study 2), and bioavailability was compared with pioglitazone 30-mg commercial tablets administered with water. In Study 3 (n = 12), the oral mucosal absorption of pioglitazone OD tablet 30 mg was determined by keeping it in the mouth for 2 min. In each study, subjects were randomized into two groups, each receiving the two regimens in a two-sequence, two-period crossover design with a 6-day washout period. Blood samples were collected over 72 h to determine plasma concentrations of unchanged pioglitazone. The 90% confidence interval for the difference in AUC0–72 and Cmax of unchanged pioglitazone following admini...

Abstract B188: Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.

Abstract Vismodegib is a first-in-class small molecule Hedgehog pathway inhibitor that is being developed for the treatment of advanced basal cell carcinoma. In a previous phase I study for patients with advanced malignancies, vismodegib was well tolerated and tumor regressions were seen in patients with advanced basal cell carcinoma and medulloblastoma. In vitro, vismodegib inhibits CYP2C8 with a Ki of 6.0 μM, which was the most potent relative to other CYP isoforms. With the average steady-state plasma concentration of total vismodegib being approximately 20 μM, inhibition of CYP2C8 by vismodegib may be important when patients are taking drugs known to be metabolized by CYP2C8. Furthermore, while vismodegib was not shown to induce CYP enzymes in vitro, it is a known teratogen. A DDI assessment with combined oral contraceptive (OC) was therefore conducted to ensure efficacious levels of OC would be maintained in patients taking vismodegib and OC in combination. This single-arm study consisted of two cohorts; 24 patients took 4 mg rosiglitazone (a known CYP2C8 substrate) and 27 patients took OC (norethindrone 1 mg/ethinyl estradiol 35 mcg, Ortho-Novum 1/35®). On Day 1 patients took rosiglitazone or OC followed by extensive PK sampling for 24 hrs. From Day 2 to Day 7 patients took 150 mg vismodegib once per day. On Day 8 patients took either vismodegib and rosiglitazone or vismodegib and OC followed by extensive PK sampling for 24 hrs. From Day 9 onward patients took vismodegib until disease progression or lack of benefit. The primary objective of this study was to evaluate the relative effect of vismodegib on AUC and Cmax for rosiglitazone and OC (ethinyl estradiol and norethindrone). The average steady state plasma concentration of total vismodegib (N=51) was 20.6 μM (range, 7.93 − 62.4 μM). There was no clinically meaningful difference in rosiglitazone PK parameters between Day 1 (without vismodegib) and Day 8 (with vismodegib) with a less than 10% difference in AUCinf and Cmax, on average. The geometric mean ratios (GMRs) for rosiglitazone AUC0−inf and Cmax were 93.1 and 93.4 with corresponding 90% confidence intervals (CIs) of (85.0, 102) and (89.4, 97.6), respectively. Concomitant administration of vismodegib with OC did not strongly impact the plasma concentrations of ethinyl estradiol or norethindrone, as evidenced by a less than 20% change in AUCinf and Cmax, on average, for both components. The GMRs for ethinyl estradiol AUC0−inf and Cmax were 99.3 and 106 with corresponding 90% CIs of (91.9, 107) and (94.8, 117), respectively while the GMRs for norethindrone AUC0−inf and Cmax were 124 and 112 with corresponding 90% CIs of (116, 132) and (101, 124), respectively. In the current study, the steady state plasma concentration of total vismodegib was above the in vitro Ki for CYP2C8. In addition, daily dosing of 150 mg vismodegib for 7 days should have been adequate to result in enzyme induction, if applicable. Overall, results from this study indicate that there was no clinically meaningful difference in AUC0−inf and Cmax for rosiglitazone, ethinyl estradiol, or norethindrone when co-administered with vismodegib. Taken together these results suggest that vismodegib can be co-administered with CYP substrates and combined oral contraceptive without the risk of a pharmacokinetic DDI. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B188.

Evaluation of in vitro serial antibiotic elution from meropenem-impregnated polymethylmethacrylate beads after ethylene oxide gas and autoclave sterilization

To determine the elution properties of meropenem and to compare the elutions of meropenem-impregnated polymethylmethacrylate (PMMA) beads without sterilization (P-M-C) to those sterilized with steam (P-M-A) and ethylene oxide gas (P-M-EO). A commercial bead mould was used to produce four groups of beads: one group without antibiotic (negative control), and three groups of meropenem-impregnated beads: P-M-C, P-M-A, and P-M-EO. The beads were placed in a phosphate buffered solution and eluent samples were collected. Concentrations of the antibiotic in eluent samples from the two sterilized groups and the control beads were determined using a microbiological assay at 1, 3, 6 and 12 hours and at 1, 2, 3, 6, 9, 12, 15, 18, 22, 26, and 30 days. The microbiological assay resulted in no zone of inhibition at all time periods for the P-M-A samples and the samples of PMMA without antimicrobial. The meropenem concentration on the eluent remained above 4 mcg/ml for 15 days in the P-M-C group and until day 18 for P-M-EO group. There was no statistical difference in AUC0-∞ (p<0.318), however significance did occur for MRT (p<0.005) when comparing P-M-C and P-M-EO with the later being higher. The meropenem incorporated in the PMMA beads eluted effectively and gradually decreased after the 24 hour peak, but remained above the concentration level of 4 mcg/ml for 15 days in the P-M-C group and until day 18 for P-M-EO group. Ethylene oxide does not adversely affect meropenem's elution from PMMA beads.

Effects of CpG-DNA from Escherichia coli on Digoxin Pharmacokinetics

Deoxyribonucleic acid (DNA) from bacteria or viruses has been reported as one of the pathogen-associated molecular patterns (PAMPs) and a substance that can induce endotoxemia-like inflammation in animals. However, there has been no report on digoxin pharmacokinetics in the inflammation induced by bacterial DNA containing unmethylated CpG motifs (CpG-DNA). In this study, we investigated the effects of CpG-DNA on digoxin pharmacokinetics. We determined the degree of lipopolysaccharide contamination in CpG-DNA solution and examined the changes in digoxin pharmacokinetics in rats after CpG-DNA administration. In addition, plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nitrite/nitrate (NOx) were determined after CpG-DNA administration (5 mg/kg, i.p.). The AUC0-24 of digoxin increased significantly on Day 1-3 and CL/F decreased on Day 1 and Day 2 after CpG-DNA administration. On Day 7 after CpG-DNA administration, there were no significant differences in AUC0-24 and CL/F compared with the control group (without CpG-DNA administration). However, Kel remained relatively unchanged throughout the experiment. Plasma TNF-alpha concentrations were significantly increased at 1 h and plasma IL-1beta concentrations were significantly decreased at 6 h after administration of CpG-DNA, while plasma NOx concentrations were significantly increased at 12 h after CpG-DNA administration, compared with the control group. These findings suggest that CpG-DNA (5 mg/kg) induces a transient inflammatory condition, and that AUC0-24 and CL/F of digoxin were altered after CpG-DNA administration. Digoxin pharmacokinetics recovered within 7 d after CpG-DNA exposure.

Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors

13016 Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sampling in Cycles 1 and 2 to assess the effect of keto on the PK of btz. No statistically significant difference in AUC0–72h for btz ± keto was observed (p=0.2248). The mean AUC0–72h ratio was 1.22 (90% CI, 0.92–1.61). The exposure-PD relationships for btz ± keto were similar (Table). Adverse events were similar in the presence and absence of keto. Conclusions: Although the AUC0–72h difference was not statistically significant, the 90% CI for the AUC0–72h ratio extends beyond the FDA- specified range of 0.80–1.25 for DDI studies, precluding a declaration of no effect. The presence of a strong CYP3A4 inhibitor increased mean btz exposure by only 22% and had no apparent effect on the exposure-PD relationship. [Table: see text] No significant financial relationships to disclose.

Broth microdilution and E-test for determining fluoroquinolone activity against Streptococcus pneumoniae.

To compare broth microdilution and E-test minimum inhibitory concentrations (MICs) of 4 fluoroquinolones against Streptococcus pneumoniae and to determine the effect of these in vitro MIC methods on the calculation of AUC00-24/MIC ratios. Levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin MICs were determined by broth microdilution (incubated in air) and E-test (incubated in CO2) for 100 clinical isolates of S. pneumoniae. MIC50, MIC90, and geometric mean MIC were calculated. Steady-state serum concentration-time profiles were simulated for once-daily, oral dosing of levofloxacin 500 mg, gatifloxacin 400 mg, moxifloxacin 400 mg, and gemifloxacin 320 mg. After correcting for protein binding, AUC0-24 of unbound drug was calculated for each regimen, and AUC0-24/MIC ratios were calculated using MIC data from both in vitro methods. Differences in MICs between methods were determined for each agent using the paired t-test (after logarithmic transformation of MICs) and the Wilcoxon signed-rank test. Differences in AUC0-24/MIC ratios were also determined using the paired t-test and the Wilcoxon signed-rank test. The level of significance for all analyses was p < 0.05. Broth microdilution and E-test MICs were within +/- 1 log2 dilution for 94%, 93%, 61%, and 35% of the isolates for levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin, respectively. Broth microdilution MICs were significantly lower than E-test MICs for all 4 agents (p < 0.001). However, a categorical change in susceptibility was seen for only 1 isolate with gatifloxacin and moxifloxacin (intermediate by broth microdilution, resistant by E-test). AUC0-24/MIC ratios were significantly higher for each regimen when MICs were determined by broth microdilution compared with E-test (p < 0.001). There is a significant difference in the activity of the newer fluoroquinolones against S. pneumoniae when MICs are determined by broth microdilution and E-test. When evaluating fluoroquinolone activity and pharmacodynamics against this organism, clinicians must be aware that MIC testing methodology may have a significant impact on the results.

Nelfinavir Suspension Obtained from Nelfinavir Tablets Has Equivalent Pharmacokinetic Profile

The pharmacokinetics of nelfinavir tablets (A) and an oral simplified nelfinavir suspension (B) were studied. Twelve healthy volunteers randomly received either five 250-mg nelfinavir tablets or a simplified oral suspension obtained from tablets dissolved in water (nelfinavir 1250 mg in 100 mL of water) in a single dose before being crossed over to the second treatment after a one-week washout period. Blood samples were drawn up to 24 h after drug administration. Nelfinavir concentrations in plasma were analyzed by a specific and validated reverse-phase high-performance liquid chromatography assay (HPLC) with UV detection, and pharmacokinetic values were determined. For the AUC0-∞with means±SD of 31.71±7.85, 30.88±10.28 (μg/L) respectively for treatments B and A, the ratio (FB/A) was of 1.1 with a C.I. of 0.90-1.24. For Cmax with means±SD of 3.1±0.6 (treatment B) and 3.2±0.8 mg/mL (treatment A), the ratio was 1.0. with C.I. of 0.92- 1.08. The two treatments evidenced no significant differences in AUC0-∞ and Cmax values and the two-one sided t-test showed that the two preparations are bioequivalent. There was no significant difference in Tmax between the liquid and tablets.Nelfinavir suspension might be a option for treating HIV-infected patients with swallowing disturbances or compliance problems.

Acetaminophen Controlled-Release Sprinkles versus Acetaminophen Immediate-Release Elixir in Febrile Children

Current acetaminophen (APAP) formulations approved for antipyretic use in children require up to five doses/day, which compromise compliance and risk breakthrough fever over 4 hours after dosing. A total of 112 evaluable febrile children received oral APAP-equivalent doses of either one dose of APAP controlled release (CR) as sprinkles on applesauce or one dose q 4 hours x 2 of APAP immediate-release (IR) elixir in an 8-hour, double-blind, double-dummy, randomized, multicenter study. Prior or concurrent antibiotic use did not significantly affect either the magnitude or the pattern of temperature reduction during the 8-hour observation period. Significantly greater aural temperature reductions were found with APAP-CR than with APAP-IR at 4 and 5 hours. However, the 8-hour AUCs of temperature reduction were not significantly different between treatments. Pharmacokinetic/pharmacodynamic modeling of APAP was performed in 8 patients with values in both treatments similar to previous results, except for expected differences in AUC0-infinity. Similar 8-hour temperature reduction for APAP-CR (one dose) and APAP-IR (two doses) demonstrates the efficacy of APAP-CR as an antipyretic in children 2 to 11 years of age. A decrease in the number of APAP daily doses and the prolonged antipyretic effect of APAP-CR may assist those who care for febrile children at home.