Compartmental Absorption Modeling and Site of Absorption Studies to Determine Feasibility of an Extended-Release Formulation of an HIV-1 Attachment Inhibitor Phosphate Ester Prodrug

Brown, Jonathan; Chien, Caly; Timmins, Peter; Dennis, Andrew B.; Döll, W; Sandefer, Erik P.; Page, Richard C.; Nettles, Richard E.; Zhu, Li; Grasela, Dennis M.

doi:10.1002/jps.23476

Cited by 50 publications

(41 citation statements)

References 23 publications

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“…BMS-663068 is a prodrug metabolized to the active moiety BMS-626529, a first-in-class attachment inhibitor that binds to HIV-1 gp120, blocking attachment of the virus to the host cell and preventing subsequent viral entry (5,6). In an ongoing phase IIb study, BMS-663068 demonstrated efficacy comparable to that of ATV/r when both were combined with TDF and RAL (11).…”

Section: Discussionmentioning

confidence: 99%

“…BMS-663068 is a prodrug that is metabolized to the active moiety BMS-626529, a first-in-class, potent HIV-1 attachment inhibitor that prevents the initial interaction between virus and host cell by binding to the viral envelope protein gp120 (5,6). This blocks attachment of the virus to the CD4 receptor of CD4 ϩ T cells (6).…”

mentioning

confidence: 99%

“…BMS-663068 is delivered as an extended-release formulation, converted to BMS-626529 by alkaline phosphatase in the gastrointestinal lumen, and then rapidly absorbed due to its efficient membrane permeability (5). The active moiety circulating in plasma, BMS-626529, is predominantly metabolized by an esterase-mediated hydrolysis pathway with contributions from a cytochrome P450 (CYP) 3A (CYP3A)-mediated oxidative pathway.…”

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confidence: 99%

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Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Zhu

Hruska

Hwang

et al. 2015

Antimicrob Agents Chemother

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BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4 ؉ T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Zhu

Hruska

Hwang

et al. 2015

Antimicrob Agents Chemother

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“…Our simulations/IVIVC for MK-0941 indicates a very similar behavior; the slowest formulation of MK-0941 results in the highest prediction error (∼20% prediction error similar to what was reported for metoprolol). In a more recent manuscript, Brown et al (19) discussed the application of GastroPlus models to guide formulation development of a HIV-1 attachment inhibitor phosphate ester prodrug. The authors also employed a regiodependent adjustment on the ASF factors to describe the absorption of the compound across the GI tract.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate

Kesisoglou

Xia

Agrawal³

2015

AAPS J

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Abstract. In vitro-in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus TM Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.

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“…BMS-663068 is administered as an extendedrelease (ER) formulation, which is delivered to the gastrointestinal tract, where it is metabolized in the small intestine by alkaline phosphatase (ALP) to release the active moiety, BMS-626529 (4). BMS-626529 is then rapidly absorbed due to its efficient membrane permeability (4).…”

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Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Landry

Zhu

Tarif

et al. 2016

Antimicrob Agents Chemother

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BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4؉ T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n ‫؍‬ 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8؉ T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the log e -transformed concentration at the end of a dosing interval (C tau ) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC 50 ) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log 10 copies/ml as a function of the log e -transformed PBAIC 50 -adjusted C tau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600-and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.) A s the management of HIV-1 infection requires lifelong treatment with sequential combination antiretroviral therapy (cART), antiretrovirals with a novel mechanism of action that can be used in combination with other agents to form active regimens following virologic failure are needed. This is particularly relevant for heavily treatment-experienced patients who, by definition, have limited remaining treatment options due to viral drug resistance, toxicity, and drug-drug interactions (1). For such patients, treatment guidelines recommend construction of a new regimen containing two or, ideally, three fully active agents where possible, on the basis of treatment history, viral drug resistance, and/or a new mechanism of action (1, 2).BMS-663068 is an oral prodrug of the first-in-class HIV-1 attachment inhibitor BMS-626529, which prevents initial viral attachment to the host CD4 ϩ T cell by binding to the viral envelope protein gp120 (3). BMS-663068 is administered as an extendedrelease (ER) formulation, which...

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Compartmental Absorption Modeling and Site of Absorption Studies to Determine Feasibility of an Extended-Release Formulation of an HIV-1 Attachment Inhibitor Phosphate Ester Prodrug

Cited by 50 publications

References 23 publications

Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

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