Co-administration of Fosamprenavir/Ritonavir Overcomes the Effect of Efavirenz Induction on Aplaviroc (APL;873140) Pharmacokinetics
K Adkison, L Fang, A Shachoy-Clark, Y Lou, S Min, V Otto, S Weller, J Begert

The purpose of this study was to compare APL pharmacokinetics when it is dosed with and without FPV/RTV or FPV/RTV/EFV. APL is a CYP3A substrate and when it is co –administered with EFV, a CYP3A inducer, this can significantly reduce APL exposures.

In the study 26 healthy subjects were enrolled in a 3 period study.

The authors concluded that APL PK parameters were significantly increased when co-administered with FPV/RTV. Also the enzyme induction caused by EFV and the enzyme inhibition caused by FPV/RTV maintained APL exposures throughout the study within a therapeutic range.

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Absence of Pharmacokinetic (PK) Drug Interaction Between Aplaviroc (APL, 873140) and Tenofovir Disoproxil Fumarate (TDF)
I Song, K Adkison, A Shachoy-Clark, L Fang, Y Lou, V Otto, S Min, S Weller, J Begert

The purpose of this study was to compare APL PK parameters when it is dosed with and without TDF. In previous studies, TDF has shown different PK interactions with other antiretroviral medications.

In this study, 28 subjects were enrolled in a 3 period study. There was a 5-7 day washout between periods 1 and 2.

The Authors concluded that there was no significant drug-drug interaction between APL and TDF.

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Pharmacokinetic (PK) Interaction Between Aplaviroc (APL;873140) and Atazanavir/Ritonavir
I Song, K Adkison, A Shachoy-Clark, J Pritchard, L Fang, Y Lou, V Otto, S Min, S Weller, J Begert

The purpose of this study was to assess the possible pharmacokinetic interaction between Atazanavir/Ritonavir (ATV/r), a CYP3A inhibitor, and Aplaviroc ( APL), a CYP3A substrate.

In the study, 42 healthy subjects were enrolled in a 2 cohort, 3 period study. There was a 7-10 day washout period between Period 1 and 2.

Results of the study showed that ATV/r significantly increased APL exposures. This shows a greater PK effect with once daily dosing of APL. Also APL had no significant effect on ATV PK. The most common adverse effect in the trial was gastrointestinal, including diarrhea, nausea and vomiting, and abdominal pain. These adverse events were more common with once daily dosing and were mainly mild to moderate.

The authors concluded that co-administration with ATV/r resulted in significant increased APL exposures, with a greater effect when APL was given as a once daily dose.

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The Pharmacokinetic Interaction Between the Entry Inhibitor Aplaviroc (APL, 873140) and Efavirenz in Healthy Adults.
K. Adkison, L Fang, A. Shachoy-Clark, Y Lou, V Otto, M Berrey, S Piscitelli, J Begert

The purpose of this study was to assess the pharmacokinetic interaction between efavirenz (EFZ), a CYP3A inducer, on Aplaviroc ( APL), an entry inhibitor. The primary focus of the study was to compare steady state APL PK parameters when it is taken with and without EFV.

In the study, 25 healthy subjects were enrolled in an open label, 2 period, single sequence inpatient study.

PK samples were collected on the last day of each treatment period.

Results of the study showed that the addition of EFV decreased APL exposures significantly (57%).

Adverse events were generally mild to moderate, mainly gastrointestinal in nature, and gastrointestinal complaints were the most common reason for early discontinuation of the trial.

The authors concluded that the combination of APL and EFV significantly decreases APL plasma concentrations due to EFV enzyme induction.

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A Study to Investigate the Interaction Between Brecanavir/Ritonavir (BCV/r) and Tenofovir (TDF) in Healthy Subjects
SL Ford, M Shelton, S Murray, M Anderson, J Ng-Cashin, M Johnson, J Begert

The purpose of this study was to assess the interaction between BCV/r, Brecanavir/Ritonavir, with TDF, Tenofovir. BCV is a potent protease inhibitor that is in development for treatment of patients with PI-resistant HIV.

In the study 35 healthy patients enrolled in a randomized unbalanced crossover study.

PK samples were collected on the last day of each study period.

The authors concluded that BCV/r 300/100mg twice daily was well tolerated whether it was taken alone or in combination with TDF 300mg once daily. Co-administration of TDF 300mg once daily with BCV/r 300/100mg increased TDF AUC by 32% and Cmax by 24%. Also co-administration of TDF 300mg once daily with BCV/r 300/100mg twice a day resulted in a 15-20% increase in BCV PK parameters and 31-39% increase in RTV exposure.

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Pharmacokinetic Interaction Between Rifabutin (RFB) and Fosamprenavir (FPV)/ Ritonavir (RTV) in Healthy Subjects.
Y Chen, SL Ford, MJ Shelton, Y Lou, J Borland, SS Min, GJ Yuen, J Begert

The purpose of this study assesses the interaction between RFB, which is used for MAC prophylaxis and for the treatment of tuberculosis in HIV infected patients, with FPV/RTV. 25-O-desacetyl-rifabutin is an active metabolite of RFB.

The authors concluded RFB dosed at 150mg every other day is recommended when co-administered with FPV/r 700/100mg twice daily. This combination of medications was well tolerated in the study.

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Effect of Food on Bioavailability of SCH 417690 in Healthy Volunteers.
A Keung, A. Sansone, M. Caceres, M. Kraan, B. Gaillac, J Begert

The purpose of this study was to assess the effects a high fat meal has on the pharmacokinetic parameters of SCH 417690, which is a CCr5 inhibitor.

In the study 20 healthy adult volunteers were enrolled in a randomized, open label, single dose, crossover study. Volunteers received a single 50mg dose of SCH 417690 under fasting conditions and with a high fat meal. (There was a washout period of at least 7 days between dose periods)

Primary Parameters

PK Parameters	Fasted(N=20)	Fed(N=20)	Ratio Estimate (%)	90% CI
Cmax (ng/ml)	241	139	58	52-65
AUC(I) ng.hr/ml)	1970	2090	107	101-113

Also Tmax was delayed from 1 hour to 3 hours with the high fat meal.

Secondary Parameters

The authors concluded that SCH 417690 could be taken with or without food, as a high fat meal decreased the rate of absorption, but not the extent of absorption.

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Pharmacokinetics of AVX754 in Combination with Trimethoprim/sulphamethoxazole
JP Sawyer, L Shiveley, R Franklin, J Begert

The purpose of this study was to assess the PK parameters of AVX754 when taken with and without TMP/SMX, as there is a high likelihood of these two medications being co-administered in practice. AVX754 is a deoxycytidine NRTI and it shares a common elimination route with TMP/SMX. BCH335 is the inactive metabolite of AVX754.

The study took place in two parts. Part 1 had 16 healthy volunteers receive a single dose of 800mg AVX754, alone and also with multiple dosing with TMP/SMX 480mg/day. The 2^nd part also had 16 subjects that received AVX754 800mg for 8 days, alone and also with multiple dosing with TMP/SMX, increased to 960mg/day.

Single dose of AVX754

PK Parameter	Alone	With TMP/SMX
AUC(SD)0-12 h.μg/ml	35.1(8.0)	58.2(11.8)
Cmax(SD)μg/ml	7.3(1.6)	9.67(1.5)

 Multiple Dosing of AVX754

 BCH335 Values (Single Dose AVX754)

BCH335 Values (Multiple Dose AVX 754)

The authors concluded that TMP/SMX increases exposure to AVX754, but the interaction is small and is unaffected by the dose of TMP/SMX, therefore there is no need for dose adjustments of AVX754.

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The Effect of Lansoprazole Acid Suppression on the Pharmacokinetics of Atazanavir in Healthy Volunteers
Tomilo DL, Smith PF, Ogundele AB, Difrancesco R, Berenson CS, Eberhardt E, Bednarczyk E, Morse GD

The purpose of this study was to evaluate the effect of lansoprazole on the pharmacokinetics of atazanavir (ATV) in healthy adult volunteers.

This study was conducted in 10 healthy adult volunteers. In the first period all subjects received a single dose of only ATV 400 mg. In the second period subjects received lansoprazole 60 mg 24 hours before a single dose of ATV 400 mg. Samples for ATV were collected at 11 time points over 24 hours and were assayed by a validated HPLC assay. Plasma concentrations for each of the 11 time points were then analyzed by non-compartmental methods.

The investigators determined that lansoprazole significantly reduced the absorption of atazanavir, with the mean AUC24 reduced by 94% ( p<0.01 ). The results were as follows: the mean (SD) AUC24 for the first period was 16.3 (9.0) uM*h, where the mean (SD) AUC24 for the second period was reduced to 0.95 (1.8) uM*h; the mean (SD) Cmax for the first period was 3.2 (1.7) uM, where the mean (SD) Cmax for the second period was reduced to 0.13 (0.19) uM (p<0.01). No significant adverse events were reported, and 9 of the 10 subjects enrolled completed the study.

Proton Pump Inhibitors (PPIs) do no Decrease Atazanavir (ATV) Trough Plasma Concentrations in HIV-Infected Patients Treated with Ritonavir Boosted Atazanavir Regimen (300/100 mg qd)
Poirier J, Guiard-Schmid J, Bonnard P, Zouai O, Meynard J, Jaillon P, Pialoux G

The purpose of this study was to determine whether the co-administration of ritonavir (RTV) boosted atazanavir (ATV) and omeprazole resulted in a decrease in atazanavir plasma concentrations in HIV-infected patients, as has been reported in healthy subjects.

In this prospective open-labeled study, plasma atazanavir concentrations were compared between 107 HIV patients who were treated with ATV/RTV 300/100 mg qd without a PPI to 17 HIV patients who were treated with ATV/RTV 300/100 mg qd with a PPI (omeprazole or rabeprazole). Atazanavir plasma concentrations were measured in all patients at either 12 hours or 24 hours (Cmin) after the last dose.

The investigators determined that in HIV infected patients, there was no decrease found in atazanavir plasma concentrations when a PPI and ATV/RTV were co-administered. The results were as follows: median ATV Cmin were 500 ng/ml in patients not receiving a PPI and 551 ng/ml in patients receiving a PPI; median ATV C12h were 1184 ng/ml in patients not receiving a PPI and 1404 ng/ml in patients receiving a PPI. They also reported that median ATV Cmin in the HIV patients not receiving a PPI were significantly lower than those reported in healthy subjects. This could be explained by a reduced gastric acid secretion in HIV patients.

The authors concluded that the significant reduction of atazanavir plasma concentrations reported in healthy subjects receiving a PPI was not confirmed in HIV patients, and thus co-administration of ATV/RTV and PPIs could be authorized. However, this study has a number of limitations including a one time sampling strategy that is very susceptible to the large degree of intra and interpatient variability seen in PI kinetics and small numbers in certain groups (only 13 and 4 in the q24 and q12h test groups, respectively). These results need to be confirmed using traditional drug-drug interaction methodology in HIV-infected subjects before altering current recommendations.

Effect of Tenofovir in Combination with Other Anti-HIV NRTIs on Intracellular Nucleotide Pools
Vela JE, Miller MD, Rhodes GR, Ray AS

The purpose of this study was to determine if tenofovir (TFV) either alone or in combination with other nucleoside/tide HIV reverse transcriptase inhibitors (NRTIs) could alter the natural dNTP or ribonucleoside triphosphate (rNTP) levels within cells.

This study was conducted using the T-cell line CEM-CCRF, as this cell model is desirable because of its high activity of nucleotide metabolizing enzymes and resulting high sensitivity to anti-metabolite agents. Tenofovir and other NRTIs were incubated in the T-cell line and natural nucleotide (dNTP and rNTP) levels were measured by LC/MS/MS.

The investigators determined that there was no significant effect on intracellular nucleotide pools upon treatment with supra-pharmacological levels of tenofovir or other NRTIs. They also determined that combinations of NRTIs, including tenofovir plus didanosine or tenofovir plus abacavir, did not result in any significant effect on intracellular nucleotide pools. The measured levels of intracellular nucleotides were all found to be in the expected range (the four rNTPs between 200 and 3,000uM, and the dNTPs between 10 and 50 uM). As a control, they determined the anti-metabolites including mycophenolic acid, ribavirin, and hydroxyurea all altered nucleotide levels as expected.

The authors concluded that tenofovir, either alone or in combination with other NRTIs, does not alter intracellular nucleotide levels.

Food Effect on the Intracellular (IC) Pharmacokinetics of Dideoxyadenosine Triphosphate (ddA-TP), the Active Metabolite of Didanosine (ddl), in Treated HIV-1 Infected Patients
Girard P, Benech H, Gendron A, Molina J, Bollens D, Allavena C, Kaul S, Couerbe P, Bernard M, Leleu G, Raffi F

The purpose of this study was to determine the food effect on intracellular dideoxyadenosine triphosphate (ddA-TP).

A multicenter, randomized, two-way cross-over study was conducted in 24 HIV-1 infected patients ( plasma viral load < 200c/ml ) receiving a 400 mg QD ddl EC-containing antiretroviral regimen. Patients received ddl EC 2 hours before (fasted) or with (fed) a light meal, for 3 periods of 14 days with no washout between periods. Intra-subject variation was evaluated in periods 2 and 3. Validated LC/MS/MS assays were then used to measure IC ddA-TP and ddl levels at day 14. A non-compartmental pharmacokinetic analysis method was used.

The investigators determined that there was a 23% reduction in IC ddA-TP AUC and a 34% reduction in plasma ddl exposure when ddl was dosed with food. It was noted that irrespective of food status, the IC ddA-TP pharmacokinetic profile was flat in contrast to the peak and valley observed in the plasma ddl pharmacokinetic profile. ddl EC was well-tolerated and viral load remained <200 c/ml throughout the study.

The authors concluded that both plasma ddl and IC ddA-TP levels were reduced when ddl was dosed with a light meal, however the clinical implications were unclear.

New Tablet Formulation of Lopinavir/Ritonavir is Bioequivalent to the Capsule at a Dose of 800/200 mg.
Zhu T, Chiu Y, Doan T, Klein C, Chang M, Brun S, Hanna G, Awni W

The purpose of this study was to assess the pharmacokinetics, tolerability and safety of a new tablet formulation of lopinavir/ritonavir (LPV/r) developed to reduce pill burden and to eliminate the refrigerated storage requirements.

This study was conducted in 15 healthy adults (12 males, 14 Caucasians) with a mean (range) age of 36 (19-53) years and weight of 77 (58-96) kg. In a randomized, cross-over pharmacokinetic study, subjects received a moderate fat meal followed by a single dose of 800/200 mg of LPV/r as either 4 tablets or 6 reference capsules. Serial blood samples were collected for 36 hours after dosing and the pharmacokinetics of the regimens were compared.

Since the 90% confidence intervals for the geometric mean ratio of test to reference Cmax and AUC fall between 0.8 and 1.25, the two formulations were determined to be bioequivalent. The percentage of subjects reporting at least one treatment-emergent adverse event with the LPV/r tablet (27%) was lower than the capsule (40%). Similarly, the percentage of subjects reporting loose stools or diarrhea was less for the tablet (13%) than the capsule (27%). All adverse events reported were mild in severity.

The authors concluded that a single 800/200 mg dose of LPV/r as the new tablet formulation was bioequivalent to the capsule. Both regimens were generally safe and well tolerated.