Drug-Drug Interaction abstracts (presented in Cannes, France)

Drug Interactions    46th ICAAC    45th ICAAC    12th Conference on Retroviruses and Opportunistic Infections (12th CROI)    43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)    IAS 2003 (International AIDS Society 2003)    10th Conference on Retroviruses and Opportunistic Infections    43rd Annual International Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL.    Drug-Drug Interaction abstracts presented at 10th Conference on Retrovirus and Opportunistic Infections, Boston, MA - Feb. 10-14, 2003    Drug-Drug Interaction abstracts presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy, Cannes, France, March 27-29, 2003     NOTE: Some of these links require a free registration with Medscape.    Use of Complementary Medicines by Patients With HIV: Full Sail Into Uncharted Waters    APHA 2000 – Drug Interactions: Decreasing the Risk    Drug Interactions and Pharmacology: Better Understanding of Present and Future Antiretroviral Therapy    Clinical Significance of Antiretroviral Drug Levels

Robert DiCenzo, Pharm.D.

Department of Pharmacy Practice
School of Pharmacy and Pharmaceutical Sciences
University at Buffalo
E-mail: robert_dicenzo@urmc.rochester.edu

Drug-Drug Interaction abstracts presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy, Cannes, France, March 27-29, 2003

Quick Links • Influence of low-dose ritonavir on the pharmacokinetics of the p-glycoprotein (P-gp) substrate digoxin • Pharmacokinetic and food effect study of once daily (OD) indinavir (IDV)/ Ritonavir (RTV) with OD enteric coated (EC) didanosine (DDI) • Rifabutin given twice weekly with ritonavir-boosted amprenavir in a once-daily HAART regimen may result in sub-therapeutic levels of rifabutin despite directly observed treatment • Elevated didanosine (ddI) plasma concentrations in HIV-infected patients treated by a tenofovir disoproxil fumarate (TDF)-enteric coated (EC)- ddI containing regimen • Evaluation of the pharmacokinetic drug interaction between capravirine and nelfinavir in healthy volunteers and HIV-infected patients

Influence of low-dose ritonavir on the pharmacokinetics of the p-glycoprotein (P-gp) substrate digoxin

Penzak et al conducted a study with 10 healthy subjects to evaluate the effect of low dose ritonavir (RTV) (200mg twice daily) on pharmacokinetic parameters of digoxin 0.4mg. Subjects received a single dose of digoxin (liquid filled capsule) 0.4mg before and after 15 days of RTV 200mg twice daily. Blood and urine samples were collected over 72 hours after each digoxin dose. The following geometric mean ratios of pharmacokinetic parameters were reported.

Digoxin AUC_0-8h and AUC_0-72h were significantly increased in the presence of low-dose RTV which may be due to enhanced secondary to P-gp inhibition. These results support the potential influence of P-gp inhibitors on the absorption of P-gp substrates. Further studies are needed to clearly identify potential P-gp mediated drug-drug interactions with protease inhibitors.

Reference
Penzak S, Shen J, Alfaro R et al. Influence of low-dose ritonavir on the pharmacokinetics of the p-glycoprotein (P-gp) substrate digoxin. Presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. [abstract 2.6]

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Pharmacokinetic and food effect study of once daily (OD) indinavir (IDV)/ Ritonavir (RTV) with OD enteric coated (EC) didanosine (DDI)

Portel et al conducted a randomized, 4-way, single dose, crossover study with 8 healthy subjects (5 males, 3 females) to evaluate the effect of food on once daily enteric coated didanosine (DDI EC) and IDV/RTV pharmacokinetics. Four regimens were given in this study: DDI EC 400mg 2 hours after breakfast (regimen A); IDV/RTV 1200/400mg with breakfast (regimen B); DDI EC 400mg plus IDV/RTV 1200/400mg 2 hours after breakfast (regimen C) or DDI EC 400mg plus IDV/RTV 1200/400mg with breakfast (regimen D). Subjects had to remain fasting for 8 hours prior to the study and received a standardized breakfast (550 kcal; 28% fat). Blood samples were collected before and up to 24 hours after treatment. Geometric mean ratios of DDI AUC_0-24h for regimen C and D tested against control group A are shown in the following table.

DDI EC plus IDV/RTV with breakfast was suggestive of bioequivalence to DDI EC 2 hours after breakfast. IDV exposure was bioequivalent in regimen B to both regimens C and D. No serious adverse event occurred with these 4 regimens.

Reference
La Porte C, Aarnoutsel R, Koopmans P et al. Pharmacokinetic and food effect study of once daily (OD) indinavir (IDV)/ritonavir (RTV) with OD enteric coated (EC) didanosine (DDI). Presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. [abstract 3.2]

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Rifabutin given twice weekly with ritonavir-boosted amprenavir in a once-daily HAART regimen may result in sub-therapeutic levels of rifabutin despite directly observed treatment

Boulanger et al conducted a directly observed treatment study to determine the rifabutin (RFB) serum levels when co-administering with once daily amprenavir (APV) and ritonavir (RTV). Patients who were antiretroviral naïve, pan-sensitive to tuberculosis (TB) medications and had completed 2 months of TB treatment were eligible to this study. Subjects were given rifabutin 150mg twice weekly, isoniazid 15mg/kg with vitamin B6 50mg twice weekly, plus once daily doses of APV 1200mg, RTV 200mg, abacavir (ABC) 300mg, and lamivudine (3TC) 300mg. Blood samples were obtained at pre-dose, and 2 and 4-hours post dose. APV and RFB plasma concentrations were measured at baseline, 2, 4, 6 and 8 weeks of therapy. When pre-dose RFB levels fell below 0.1 ug/mL, the dose was increased in increments of 150mg. The results of 2 patients were reported at his meeting. In the presence of APV and RTV, pre-dose levels of RFB were sub-therapeutic (<0.05 ug/ml) despite 2 dose escalations (150 mg to 300 mg to 450 mg). Further studies are needed to determine the optimal dosing interval of RFB for patients receiving HAART with RTV-boosted regimens.

Reference
Boulanger C, Ha B, Desrosiers M et al. Rifabutin given twice weekly with ritonavir-boosted amprenavir in a once-daily HAART regimen may result in sub-therapeutic levels of rifabutin despite directly observed treatment. Presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. [abstract 8.5]

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Elevated didanosine (ddI) plasma concentrations in HIV-infected patients treated by a tenofovir disoproxil fumarate (TDF)-enteric coated (EC)- ddI containing regimen

Lamotte et al conducted a study with 54 HIV infected patients (85% male) to report plasma concentrations when co-administrating ddI EC 400mg daily and TDF 300mg daily. Subjects were recommended to take ddI (fasting) and TDF (with a meal). Other concomitant antiretroviral medications included nucleoside reverse transcriptase inhibitors (25%), non-nucleoside reverse transcriptase inhibitors (15%), at least one protease inhibitors (54%), or at least one ritonavir boosted PI (6%). Median plasma concentrations of ddI and TDF were shown in the following table.

When compared to historical data, plasma concentrations of ddI were significantly increased (p=0.003) while TDF plasma concentrations were not altered significantly. When combined with TDF in HIV infected patients, plasma concentrations of ddI were significantly higher than controls. More study is necessary before recommending dose modification of ddI.

Reference
Lamotte C, Kirstetter M, Landman R et al. Elevated didanosine (ddI) plasma concentrations in HIV-infected patients treated by a tenofovir disoproxil fumarate (TDF)-enteric coated (EC)-ddI containing regimen. Presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. [abstract 8.6]

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Evaluation of the pharmacokinetic drug interaction between capravirine and nelfinavir in healthy volunteers and HIV-infected patients

Raber et al conducted a 2-phase study to evaluate the pharmacokinetic of capravirine (CPV) and nelfinavir (NFV) co-administration.

Phase 1 was an open-label, multiple dose, parallel group design with healthy subjects. In group 1, subjects received NFV 1250mg twice daily for 7 days followed by NFV 1250mg twice daily plus CPV 1400mg twice daily for 7 days. Subjects in group 2 received CPV 1400mg twice daily for 7 days followed by CPV 1400mg twice daily plus NFV 1250mg twice daily for 7 days. Doses were administered within 15 minutes of completing a meal. Blood samples were collected on days 7 and 14 at the following time points: pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 hours post-dose. CPV results are reported in table 1 and NFV results are reported in table 2.

The second study was an open-label, randomized, multi-center study with treatment naïve HIV infected patients. In group 1, subjects received CPV 1400mg plus NFV 1250mg plus Combivir™ (lamivudine 150mg/zidovudine 300mg) twice daily. Subjects in group 2 received CPV 2100mg plus NFV 1250mg plus Combivir™ twice daily. All doses were administered with food. Blood samples were collected on day 8 at the following time points: pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 hours post-dose. CPV results are reported in table 1.

Table 1: CPV Geometric Means for PK parameters

	Healthy volunteers			HIV infected patients
Parameter	CPV 1400mg BID (95% CI)	CPV 1400mg BID+NFV 1250mg BID (95% CI)	Geometric mean ratio (90% CI)	CPV 1400mg BID + NFV 1250mg BID + Combivir (95% CI)	CPV 2100mg BID + NFV 1250mg BID + Combivir (95% CI)
n	12	12	-	22	20
AUCτ(h•mg/L)	13.7 (10.6-17.8)	32.7 (27.4-39.0)	2.38 (1.96-2.90)	21.8 (16.0-29.8)	27.9 (18.4-42.3)
Cmax (mg/L)	3.73 (2.91-4.77)	6.86 (5.69-8.27)	1.84 (1.59-2.13)	4.35 (3.27-5.79)	5.44 (3.76-7.87)
Tmax (h)*	2.5 (1.5-4.0)	2.5 (1.5-4.0)	0.00 (0.00-1.00)	2.8 (1.0-4.0)	2.8 (0.0-6.0)
C12 (mg/L)	0.10 (0.07-0.14)	0.37 (0.26-0.53)	3.63 (2.67-4.92)	0.37 (0.24-0.55)	0.48 (0.32-0.71)
T1/2 (h)	2.07 (1.64-2.60)	1.99 (1.67-2.36)	0.99 (0.77-1.21)	2.83 (2.42-3.30)	2.43 (2.04-2.90)
Cl/F (L/h)	102 (78.8-132)	42.9 (35.9-51.1)	0.42 (0.34-0.51)	64.1 (46.9-87.6)	66.8 (47.0-94.9)

*median (range) and median difference (90% CI)

Table 2:Nelfinavir Geometric Means (95% CI) for PK parameters

Parameter	NFV 1250mg BID	NFV 1250mg BID +CPV 1400mg BID	Geometric mean ratio (90% CI)
n	11	11	-
AUCτ(h•mg/L)	32.9 (24.2-44.6)	34.8 (28.6-42.3)	1.06 (0.91-1.23)
Cmax (mg/L)	5.10 (4.06-6.41)	5.35 (4.76-6.02)	1.05 (0.91-1.21)
Tmax (h)*	2.5 (1.5-3.0)	3.0 (2.0-4.0)	0.97 (0.00-1.00)
C12 (mg/L)	0.72 (0.43-1.23)	0.89 (0.64-1.25)	1.24 (0.95-1.60)
Cl/F (L/h)	38.1 (28.1-51.6)	35.9 (29.5-43.7)	0.94 (0.81-1.09)
M8:NFV AUCτ molar ratio§	0.36 (0.28-0.44)	0.27 (0.22-0.33)	0.75 (0.65-0.87)

* median (range) and median difference (90% CI)
§ n=10

PK of NFV was not significantly altered when administered with CPV in healthy subjects; however, a reduction of M8 was observed. Plasma concentrations of CPV were increased by approximately 2-fold when co-administered with NFV in healthy subjects. At 1400 mg BID with NFV, the CPV AUC appears lower in HIV infected subjects compared to healthy individuals. CPV 1400mg BID C12 concentrations were similar in healthy volunteers and HIV infected patients when combined with NFV and in both HIV groups CPV C12 concentrations remained above the protein binding adjusted median IC50 (0.037 mg/L) for NNRTI-resistant HIV.

Reference
Raber S, Reynolds R, Heel B et al. Evaluation of the pharmacokinetic drug interaction between capravirine and nelfinavir in healthy volunteers and HIV-infected patients. Presented at 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. [abstract 8.8]

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