Preclinical Assessment Addressing Intravenous Administration of a [68Ga]Ga-PSMA-617 Microemulsion: Acute In Vivo Toxicity, Tolerability, PET Imaging, and Biodistribution.

It has been herein presented that a microemulsion, known to be an effective and safe drug delivery system following intravenous administration, can be loaded with traces of [68Ga]Ga-PSMA-617 without losing its properties or causing toxicity. Following tolerated IV injections the capability of the microemulsion in altering [68Ga]Ga-PSMA-617 distribution was presented at 120 min post injection based on its ex vivo biodistribution results.

In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model.

There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 µM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 µM) in the distal duodenum and in proximal jejunum (0.00-0.43 µM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.

Population Pharmacokinetic Modeling and Exposure-Response Assessment for the Antibody-Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON-1 Study.

The efficacy of the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin's lymphoma in the randomized phase III ECHELON-1 study. Population pharmacokinetic (PK) and exposure-response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy end points in ECHELON-1. The influence of patient-specific factors on the PK of the ADC and the microtubule-disrupting payload monomethyl auristatin E (MMAE) was investigated; none of the significant covariates had a clinically relevant impact. Exposure-response analyses evaluated relationships between time-averaged area under the curve (AUC; ADC, MMAE) and efficacy end points (ADC) or safety parameters (ADC, MMAE). Exposure-efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposure-safety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony-stimulating factor primary prophylaxis.

Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir.

BACKGROUND: Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy. METHODS: Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate. RESULTS: Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies. CONCLUSIONS: The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.

Rapid determination of hexapeptides by hydrophilic interaction LC-MS/MS for in vitro skin-penetration studies.

BACKGROUND: A sensitive analytical method is needed for assessing penetration of topically applied peptides for in vitro skin-penetration studies. RESULTS: A rapid hydrophilic interaction LC (HILIC)-MS/MS method for analyzing the polar peptides Ac-EEMQRR-amide and H2N-EEMQRR-amide in various skin layers and matrices has been developed and evaluated. The matrices included emulsion, receptor fluids, cotton-tipped applicators, stratum corneum tape strips, epidermis and dermis of the skin. Stable isotopically labeled analogues were used as internal standards to correct for recovery and matrix effects. A HILIC-SPE procedure was optimized to minimize significant ion suppression in the more complex matrices. CONCLUSION: This HILIC-MS/MS method is applicable to the determination of Ac-EEMQRR-amide and H2N-EEMQRR-amide in complex skin samples and other matrices generated during in vitro skin-penetration studies.

Simultaneous population pharmacokinetic modelling of atazanavir and ritonavir in HIV-infected adults and assessment of different dose reduction strategies.

OBJECTIVES: The objective of this study was to develop a simultaneous population pharmacokinetic (PK) model to describe atazanavir/ritonavir (ATV/RTV) PK (300/100 mg) and to assess the effect of RTV dose reduction on ATV PK. Simulations of ATV concentration-time profiles were performed at doses of ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily. METHODS: A total of 288 ATV and 312 RTV plasma concentrations from 30 patients were included to build a population PK model using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.2 software. RESULTS: A one-compartment model with first-order absorption and lag-time best described the data for both drugs in the final simultaneous model. A maximum-effect model in which RTV inhibited the elimination of ATV was used to describe the relationship between RTV concentrations and ATV clearance (CL/F). An RTV concentration of 0.22 mg/L was associated with 50% maximum inhibition of ATV CL/F. The population prediction of ATV CL/F in the absence of RTV was 16.6 L/h (relative standard error, 7.0%), and the apparent volume of distribution and absorption rate constant were 106 L (relative standard error, 8%) and 0.87 per hour (fixed), respectively. Simulated average ATV trough concentrations at ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg once daily were 45%, 63%, and 33% lower, respectively, than that of the standard dose. CONCLUSION: Although simulated median ATV trough concentrations after dose reductions were still more than the ATV minimum effective concentration (2.9-, 1.9-, and 3.6-fold for ATV/RTV 300/50 mg, 200/50 mg, and 200/100 mg, respectively); our modeling predicted a high proportion of individuals with subtherapeutic trough concentrations on the 200/50 mg dose. This suggests that 300/50 mg and 200/100 mg dosing are preferred candidate regimens in future clinical studies.

External validation of the bilirubin-atazanavir nomogram for assessment of atazanavir plasma exposure in HIV-1-infected patients.

Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95-100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.

Synthesis and comparative assessment of a labeled RGD peptide bearing two different 99mTc-tricarbonyl chelators for potential use as targeted radiopharmaceutical.

During the past decade radiolabeled RGD-peptides have been extensively studied to develop site-directed targeting vectors for integrins. Integrins are heterodimeric cell-surface adhesion receptors, which are upregulated in cancer cells and neovasculature during tumor angiogenesis and recognize the RGD aminoacid sequence. In the present study, we report the synthesis and development of two derivatives of the Nε-Lys derivatized cyclic Arg-Gly-Asp-D-Phe-Lys peptide, namely of cRGDfKHis and cRGDfK-CPA (CPA: 3-L-Cysteine Propionic Acid), radiolabeled via the [(99m)Tc(H(2)O)(3)(CO)(3)](+) metal aquaion at a high yield even at low concentrations of 10-5M (>87%) for cRGDfK-10-5M (>93%) for cRGDfK-CPA. Radiolabeled peptides were characterized with regard to their stability in saline, in His/Cys solutions, as well as in plasma, serum and tissue homogenates and were found to be practically stable. Internalization and efflux assays using αvß3-receptor-positive MDA-MB 435 breast cancer cells showed a good percentage of quick internalization (29.1 ± 9.8% for (99m)Tc-HiscRGDfK and 37.0 ± 0.7% for (99m)Tc-CPA-cRGDfK at 15 min) and no retention of radioactivity for both derivatives. Their in vivo behavior was assessed in normal mice and pathological SCID mice bearing MDA-MB 435 ανß3 positive breast tumors. Both presented fast blood clearance and elimination via both the urinary and hepatobiliary systems, with (99m)Tc-His-cRGDfK remaining for a longer time than (99m)Tc-CPA-cRGDfK in all organs examined. Tumor uptake 30 min pi was higher for (99m)Tc-CPAcRGDfK (4.2 ± 1.5% ID/g) than for (99m)Tc-His-cRGDfK (2.8 ± 1.5% ID/g). Dynamic scintigraphic studies showed that the tumor could be visualized better between 15 and 45 min pi for both radiolabeled compounds but low delineation occurred due to high abdominal background. It was finally noticed that the accumulated activity on the tumor site was depended on the size of the experimental tumor; the smaller the size, the higher was the radioactivity concentration.

A population pharmacokinetic-pharmacogenetic analysis of atazanavir.

Atazanavir is a first-line HIV protease inhibitor commonly co-dosed with ritonavir. Ritonavir inhibits atazanavir metabolism, decreasing variability and increasing plasma concentrations. However, ritonavir use results in higher costs and increased drug-related adverse events. Elucidating atazanavir pharmacokinetics might allow for individualized ritonavir boosting. We previously demonstrated that genetically determined CYP3A5 nonexpression was associated with slower atazanavir clearance CL/F and higher trough concentrations. This effect was prominent in non-African-American men but absent in African-Americans. The present study considers additional genetic predictors of atazanavir CL/F with a focus on race differences. Nine polymorphisms in CYP3A4, ABCG2, NR1I2 (PXR), and SLCO1B1 were evaluated; 330 plasma samples from 30 HIV-negative volunteers, balanced by sex, race, and CYP3A5 expressor status, were available. Analyses were performed using nonlinear mixed-effects modeling (NONMEM). The following factors were univariately associated with atazanavir CL/F (% effect) : African-American race (decreased 35%), female sex (decreased 25%), older age (decreased 1.7%/year), CYP3A5 nonexpressors (decreased 26%), ABCB1 CGC haplotype carriers (1236C/2677G/3435C) (decreased 33%), and CYP3A4*1B carriers (decreased 31%). However, an independent genetic explanation for the differential race effect could not be identified. An interaction was observed with PXR 63396 C>T and CYP3A5 expressor status (p=0.0002). CYP3A5 nonexpressors with a PXR 63396 CC genotype had 37% slower CL/F versus those with CT or TT genotypes. For CYP3A5 expressors, those with a PXR 63396 CC genotype had 63% faster CL/F versus those with CT or TT genotypes. Although this study has as its main limitation a small overall sample size, these results nonetheless provide new leads and impetus to evaluate ways to individualize the need for ritonavir boosting using demographic and genetic predictors of atazanavir pharmacokinetics.

Comparison of extraction procedures for assessment of matrix effect for selective and reliable determination of atazanavir in human plasma by LC-ESI-MS/MS.

A comparative study with three conventional extraction techniques namely protein precipitation (PP), liquid-liquid extraction (LLE) and solid phase extraction (SPE) has been demonstrated to assess the magnitude of matrix interference by post-column analyte infusion and post extraction analyte spiking for the determination of atazanavir from human plasma. Severe ion suppression observed in PP and to a lesser extent in LLE was circumvented by SPE on LiChrosep Sequence extraction cartridge. Based on these observations a selective, rugged and high throughput SPE-LC-MS/MS method has been developed for reliable determination of atazanavir in human plasma. The chromatographic separation was achieved on a Hypersil Gold C18 (50mm×4.6mm, 5µm) analytical column using 5mM ammonium formate in water:methanol (10:90, v/v) as the mobile phase under isocratic conditions. The method was validated over a wide dynamic concentration range of 10-6000ng/mL. The mean relative recovery and absolute matrix effect across quality controls were 84.9 and 93.2%, respectively. The precision value for relative matrix effect between eight different lots of plasma, expressed as %CV of the slopes of the calibration lines was 2.41. The stability of atazanavir under different storage conditions varied from -8.4 to 5.4%. The method was successfully applied to a bioequivalence study of 300mg atazanavir capsule formulation in 24 healthy Indian males under fasting condition.

Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus.

BACKGROUND: Hepatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. The incidence of acute hepatitis C in the United States peaked near 50,000 cases in the late 1980s but has stabilized since 2003 to less than 5,000 cases annually. The combination of pegylated interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV. Protease inhibitors telaprevir and boceprevir were approved by the FDA in May 2011 for the treatment of hepatitis C genotype 1 in combination with peginterferon and ribavirin. OBJECTIVE: To review the phase 3 trials for telaprevir and boceprevir and provide managed care considerations. METHODS: A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "boceprevir" or "telaprevir" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Additional information was obtained from the FDA website. RESULTS: Three phase 3 trials are available for telaprevir, which provided data that were the basis for FDA approval. Boceprevir demonstrated efficacy and safety in 2 pivotal phase 3 trials. Both agents demonstrated statistically significantly higher rates of virologic response compared with the standard of care involving peginterferons and ribavirin. Telaprevir and boceprevir also demonstrated efficacy in the treatment of patients who had previously failed dual therapy for hepatitis C. Safety concerns for both agents include anemia, drug interactions, skin rashes, and gastrointestinal adverse events. CONCLUSIONS: Decision makers have many factors to consider in developing a strategy around hepatitis C. Increased drug costs, patient management, adherence, comparative safety and efficacy, and appropriate utilization management controls are important issues. Payers may consider developing clinical programs to encourage adherence and appropriate use and leverage an appropriate channel to ensure cost-effective therapy.

[Evidence-based therapeutic drug monitoring of atazanavir]. / Niveau de preuve du suivi therapeutique pharmacologique de l'atazanavir.

The HIV protease inhibitor atazanavir presents a wide inter-individual variability related to an intense hepatic metabolism. Dose-dependent elevations of bilirubin have been frequently reported with atazanavir. Relative to literature, the atazanavir therapeutic drug monitoring can it be proposed? In naïve HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a plasma trough concentration (C(min)) of atazanavir >200 ng/mL. Studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of the virologic response with a threshold value around 200 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 hyperbilirubinemia was more frequently associated with C(min) > 750-800 ng/mL. Non-randomized studies have reported the interest of atazanavir therapeutic drug monitoring to optimize the virologic response and prevent severe bilirubin elevations. Therefore, the level of evidence of the interest of atazanavir therapeutic drug monitoring is recommended.

Cilengitide: an RGD pentapeptide ανß3 and ανß5 integrin inhibitor in development for glioblastoma and other malignancies.

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανß3 and ανß5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

Atazanavir metabolism according to CYP3A5 status: an in vitro-in vivo assessment.

The current study was a follow-up to an in vivo study in which atazanavir oral clearance was shown to be dependent on genetically determined CYP3A5 expression status, but only in non-African Americans. The aim of this study was to identify atazanavir metabolites generated by CYP3A5 and to evaluate this metabolite pattern in the African-American versus non-African-American CYP3A5 expressors from the previous study. First, the in vitro metabolism of atazanavir was evaluated using human liver microsomes (HLM) and CYP3A4 and CYP3A5 isoforms. Second, the metabolite pattern generated by CYP3A5 was evaluated in human plasma samples from the previous study. Atazanavir metabolites were analyzed using liquid chromatography-tandem mass spectrometry methods. Metabolite areas under the time-concentration curves (AUCs) were normalized to atazanavir AUC to generate an AUC ratio. Sixteen metabolites were observed in human liver microsomal incubations representing five "phase I" biotransformation pathways. Mono-oxidation products (M1 and M2) were formed by CYP3A5 at a faster rate than CYP3A4 by 32- and 2.6-fold, respectively. This finding was replicated in HLM from a genetically determined CYP3A5 expressor versus nonexpressor. In the in vivo samples, the M1 and M2 AUC ratios were approximately 2-fold higher in CYP3A5 expressors versus nonexpressors (P < 0.05), and the difference was similar in African Americans and non-African Americans. Thus, CYP3A5 produced a unique metabolite "signature" for atazanavir in vitro and in vivo, independent of race. Therefore, other pharmacological factors are likely to explain the apparent lack of effect of genetically determined CYP3A5 expressor status on atazanavir oral clearance in African Americans from the previous study.

Structural assessment and biological evaluation of two N3S bombesin derivatives.

The aim of the present study is the evaluation of the (99m)Tc complexes of two bombesin-like peptides: Gly1'-Gly2'-Cys3'-Aca-BN[2-14] (BN-1.1) and Gly1'-Gly2'-Cys3'-Aca-BN[7-14] (BN-1.1p). The BN derivatives were synthesized according to the solid phase peptide synthesis method, and characterized by ESI-MS and NMR. (185/187)Re-BN-1.1 and (185/187)Re-BN-1.1p were also identified by ESI-MS and NMR. The (99m)Tc complexes were stable over time in human plasma, while they degraded rapidly in kidney-liver homogenates. The peptides and their (99m)Tc complexes showed high affinity for the human GRP receptors expressed in PC-3 cells. The rate of internalization of these radiolabeled biomolecules was found to be time-dependent. Also, it was found that there was no long-term retention of the radioactive metabolites into the cells. Tissue distribution of the radiopeptides was evaluated in normal mice and in prostate cancer experimental models. Significant uptake of radioactivity was observed in the pancreas of PC-3 tumor-bearing SCID mice. Dynamic studies of both radiopeptides showed satisfactory tumor images.

Extension of the SAEM algorithm for nonlinear mixed models with 2 levels of random effects.

This article focuses on parameter estimation of multilevel nonlinear mixed-effects models (MNLMEMs). These models are used to analyze data presenting multiple hierarchical levels of grouping (cluster data, clinical trials with several observation periods, ...). The variability of the individual parameters of the regression function is thus decomposed as a between-subject variability and higher levels of variability (e.g. within-subject variability). We propose maximum likelihood estimates of parameters of those MNLMEMs with 2 levels of random effects, using an extension of the stochastic approximation version of expectation-maximization (SAEM)-Monte Carlo Markov chain algorithm. The extended SAEM algorithm is split into an explicit direct expectation-maximization (EM) algorithm and a stochastic EM part. Compared to the original algorithm, additional sufficient statistics have to be approximated by relying on the conditional distribution of the second level of random effects. This estimation method is evaluated on pharmacokinetic crossover simulated trials, mimicking theophylline concentration data. Results obtained on those data sets with either the SAEM algorithm or the first-order conditional estimates (FOCE) algorithm (implemented in the nlme function of R software) are compared: biases and root mean square errors of almost all the SAEM estimates are smaller than the FOCE ones. Finally, we apply the extended SAEM algorithm to analyze the pharmacokinetic interaction of tenofovir on atazanavir, a novel protease inhibitor, from the Agence Nationale de Recherche sur le Sida 107-Puzzle 2 study. A significant decrease of the area under the curve of atazanavir is found in patients receiving both treatments.

Maraviroc: in vitro assessment of drug-drug interaction potential.

AIMS: To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs). METHODS: Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyptrade mark population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic. RESULTS: Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a K(m) of 21 microM and V(max) of 0.45 pmol pmol(-1) min(-1) in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a K(m) of 13 microM and a V(max) of 3 pmol pmol(-1) CYP min(-1). Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI. CONCLUSION: Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyptrade mark has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.

Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable.

BMS-232632 is a potent human immunodeficiency type 1 (HIV-1) protease inhibitor with a half-life that allows for once-daily dosing. A concentration of 4 times the viral 50% effective concentration (EC(50) [i.e., approximately EC(95)]) administered as a continuous infusion in vitro provides virtually complete suppression of viral replication. This exposure, modeled in vitro as once-daily administration with oral absorption, allows ongoing viral replication. An exposure 4 times as large was calculated to be necessary to provide virus suppression equivalent to the continuous-infusion exposure. These experiments demonstrated that concentration above a threshold (time > 4xEC50) is the pharmacodynamically linked variable for this HIV-1 protease inhibitor. Protein-binding experiments demonstrated that the EC(50) was increased 13.4 times by the addition of human binding proteins. Monte Carlo simulation of protein binding-adjusted pharmacokinetic data from volunteers demonstrated that 64%-70% of a simulated population (n = 3000) would achieve virus suppression with 400-600 mg of BMS-232632 given once daily, if the viral EC(50) were < or = 1 nM.