Drug-drug Interaction Abstracts

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 10th Conference on Retrovirus and Opportunistic Infections, Boston, MA - Feb. 10-14, 2003

Quick Links •Pharmacokinetic interaction between rifampin and the twice-daily combination of indinavir and low-dose ritonavir in HIV-infected patients •Two-year evaluation of the interactions between antiretroviral medication and cyclosporine in HIV+ liver and kidney transplant recipients •Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir •A two-way drug interaction between lopinavir/ritonavir and phenytoin •Pharmacokinetics of nelfinavir (Viracept 250mg tablet): effect of food intake on single-dose PK parameters •Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects •Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction •Lack of interaction between stavudine extended-release formulation and tenofovir disoproxil fumarate •Enfuvirtide: investigations on the drug interaction potential in HIV-infected patients

Pharmacokinetic interaction between rifampin and the twice-daily combination of indinavir and low-dose ritonavir in HIV-infected patients

Justesen et al conducted a prospective, controlled study with 6 HIV infected patients to evaluate the effect of rifampin (a CYP 3A4 inducer), ritonavir (RTV), and indinavir (IDV) coadministration. Subjects received IDV/RTV 800/100mg and two nucleoside analogues. The steady state PK of IDV and RTV were calculated both before and after administration of rifampin 300mg daily for 4 days. Only subjects with IDV C12h > 400 ng/ml could participate. The following PK parameters were reported:

IDV Results

IDV Parameters	IDV/RTV 800/100mg Median (Range)	IDV/RTV 800/100mg +Rifampin Median (Range)	Wilcoxon signed rank test
Cmax(ng/mL)	11261 (7404-17069)	10116 (2864-10913)	p=0.063
C12h(ng/mL)	837 (406-2154)	112 (54-258)	p=0.031
Tmax(h)	1.0 (0.5-2.0)	1.0 (0.5-3.0)	p=1.0
T1/2β(h)	2.8 (2.2-2.9)	1.7 (1.5-2.3)	p=0.063

Ritonavir Results

RTV Parameters	IDV/RTV 800/100mg Median (Range)	IDV/RTV 800/100mg +Rifampin Median (Range)	Wilcoxon signed rank test
Cmax(ng/mL)	1654 (776-3397)	1021 (87-1676)	p=0.031
C12h(ng/mL)	431 (117-686)	27 (13-60)	p=0.031
Tmax(h)	4.0 (1.0-6.0)	3.0 (1.0-4.0)	p=0.5
T1/2β(h)	3.4(2.5-3.9)	1.6 (1.4-2.2)	p=0.031

Rifampin significantly reduced IDV and RTV trough plasma concentrations (p=0.031) which may result in a clinically significant interaction. Although approximately 8 samples were drawn over the dosing interval, area under the concentration-time curve was not reported. Co-administration of rifampin and IDV/RTV was not recommended.

Reference
Justesen U, Andersen A, Klitgaard N, et al. Pharmacokinetic interaction between rifampin and the twice-daily combination of indinavir and low-dose ritonavir in HIV-infected patients. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 542].

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Two-year evaluation of the interactions between antiretroviral medication and cyclosporine in HIV+ liver and kidney transplant recipients

Frassetto et al conducted pharmacokinetic studies on 17 HIV+ subjects who underwent liver and kidney transplantation and compared the results to historical controls. Subjects were receiving protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) or both, and cyclosporine (CsA) initiated post transplant. Data was obtained pre-transplantation, week 1-2, 4-8, 12, 28, 52 and 2 years post transplantation. Dosing interval AUCs of PIs pretransplantation tended to be 20% below the literature mean AUC and further decreased for 12 weeks post transplantation before returning to pre-transplantation levels. However, Lopinavir and ritonavir AUCs were 5-6 and 3 times higher than literature values, respectively, up to 12 weeks after transplantation. AUCs of NNRTIs (efavirenz and nevirapine) were generally not affected by CsA. PIs tended to increase AUC of CsA requiring a greater than 75% dose adjustment. NNRTIs did not affect the AUC of CsA. Since the data provided by this study was generalized to a whole class of antiretrovirals, results should be applied to individual antiretroviral medications with caution. This trial gives preliminary evidence that administration of PIs with CsA may require CsA dose adjustment. Prospective studies designed to evaluate PI and CsA coadministration are necessary.

Reference
Frassetto LA, Baloum M, Roland ME et al. Two-year evaluation of the interactions between antiretroviral medications and cyclosporine in HIV+ Liver and Kidney transplant recipients. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 540].

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Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir

Klein et al conducted a multiple-dose, sequential, open-label, single-center, non-fasting study with 13 subjects to evaluate the pharmacokinetic effects of lopinavir/ritonavir (LPV/r) and nelfinavir (NFV) co-administration. Each subject received LPV/r 400/100mg twice daily for 21 days. NFV 1000mg twice daily was co-administered with LPV/r on the evening of day 11 until the morning of day 21. From the evening of day 21 through day 35, NFV 1250mg twice daily was given alone. Results include those listed below:

Regimen	AUC12 (h•mcg/mL)
	LPV	RTV	NFV	M8
LPV/r or NFV1250mg alone	95.9	5.3	24.2	6.4
LPV/r with NFV 1000mg	70.0*	4.1*	25.8	22.3*

*p<0.05 compared to LPV/r or NFV alone

Bioavailability of LPV/r was significantly decreased when co-administered with NFV. Dose adjustment of LPV/r might be necessary for effective treatment. NFV 1000mg twice daily with LPV/r was bioequivalent to NFV 1250mg twice daily given alone (AUC₁₂ geometric mean ratio = 1.07; 90% CI = 0.95-1.19). There was no significant change in NFV concentration. However, its metabolite, hydroxyl-t-butylamide (M8), was significantly increased with co-administration of LPV/r. Further studies are required to define the role of M8 in HIV therapy.

Reference
Klein C, Bertz R, Ashbrenner E, et al. Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 536].

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A two-way drug interaction between lopinavir/ritonavir and phenytoin

Lim et al conducted an open-label, randomized, cross-over design study with 24 volunteers to evaluate the multiple-doses pharmacokinetic interaction between lopinavir/ritonavir (LPV/R) and phenytoin (PHT). Group A included twelve patients who received LPV/R 400/100mg twice daily on day 1-10; then, LPV/R 400/100mg twice daily and PHT 300mg daily on day 11-22. Group B had twelve patients who received PHT 300mg daily on day 1-11; then, PHT 300mg daily and LPV/R 400/100mg twice daily on day 12-23. Four subjects in group B did not complete the study. Results include those listed below:

	Day 11	Day 22	Geometric Mean Ratio (90% CI)	p-value
LPV AUC0-12h	70.89±36.96	49.61±25.09	0.67 [0.53-0.85]	0.011
RTV AUC0-12h	3.08±2.79	1.99±1.09	0.72 [0.54-0.97]	0.074
PHT AUC0-24h	191.00±89.21	147.75±104.54	0.69 [0.57-0.84]	0.009

Co-administration of LPV/R and PHT resulted in a two-way drug interaction in which both LPV/R and PHT plasma concentrations were significantly decreased. Dose adjustment might be needed to ensure effective treatment.

Reference
Lim ML, Min SS, Eron JJ, et al. A two-way drug interaction between lopinavir/ritonavir and pheytoin. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 535].

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Pharmacokinetics of nelfinavir (Viracept 250mg tablet): effect of food intake on single-dose PK parameters

Petersen et al conducted a phase I, randomized, open-label, cross-over and single-dose study with 24 normal volunteers to evaluate the effect of total kilocalories and fat content on the pharmacokinetics of nelfinavir 1250mg given as a single dose. Subjects received nelfinavir 1250mg four times at one-week intervals. Pharmacokinetic profiles were collected over 12 hours after each dose. Each subject was assigned to 4 different food intakes protocol: fasting, 125 kcal with 20% fat, 500 kcal with 20% fat and 1000 kcal with 50% fat. Results include those listed below:

	Fasting	125kcal/20%fat	500kcal/20%fat	1000kcal/50%fat
AUC12hr• mcg/ml (x fasting)	9.04	20.0 (2.2 x)	25.5 (2.8 x)	38.9 (4.3 x)
AUCinf hr• mcg/ml (x fasting)	10.6	23.1 (2.2 x)	33.4 (3.1 x)	55.3 (5.2 x)
M8 AUCinf/NFV AUCinf (%)	26.5	15.8	15.3	20.8

Varying the total kilocalories and fat content intake had a significant effect on nelfinavir plasma concentrations. M8 concentrations also increased with increasing food intake but the ratio of M8/Nelfinavir did not. Further study is needed to define the effect of food intake on nelfinavir pharmacokinetics.

Reference
Petersen C, Pun E, Strada R, Daniels E, et al. Pharmacokinetic of nelfinavir (Viracept 250mg tablet): effect of food intake on single-dose PK parameters. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 544].

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Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects

Part I

Tackett et al conducted an open-label, randomized study with 34 healthy subjects to evaluate if efavirenz (EFV) had an effect on atazanavir (ATV) exposure. They all received ATV 400mg daily on days 1-6 days, then either 600mg ATV daily and EFV 600mg daily (2 hours later) (Regimen A) or ATV 300mg daily, ritonavir (RTV) 100mg daily and EFV 600mg daily (2 hours later) (Regimen B) on days 7-20. Both ATV and RTV doses were administered with a light meal. Twenty-three subjects completed the study and results include those listed below:

Regimen	AUC24h geometric mean ratio (Day 20/ Day 6) (95% CI)
A	0.79 (0.56, 1.11)
B	1.39 (1.02, 1.88)

Neither regimen that included EFV was bioequivalent to ATV administered alone. However, combining EFV with either regimen appears to provide adequate exposure and both combination regimens were generally safe and well tolerated. More study is necessary to in HIV infected patients to determine these ATV regimens are adequate when combined with EFV.

Part II

Tackett et al conducted an open-label, non-randomized study in 22 healthy adult females to assess the effect of atazanavir (ATV) 400mg on ethinyl estradiol (EE) and norethindrone (NE). Subjects received an oral regimen of ortho-novum® 7/7/7 from days 1-29 and ATV 400mg daily was administered from days 16-29. Results were as follows:

	Day 1	Day 29	Geometric mean Ratio (Day 29 / Day1) (95% CI)
Norethindrone AUC24h (pg•h/mL)	72905	152820	2.10 (1.68, 2.62)
Ethinyl estradiol AUC24h (pg•h/mL)	1020	1512	1.48 (1.31, 1.68)

Co-administration of ATV 400mg and ortho novum® 7/7/7 resulted in an increase in NE AUC of 110% and a 48% increase in the AUC of EE; however, the clinical significance of this interaction are unknown.

Reference
Tackett D, Child M, Agarwala S, et al. Atazanavir: a summary of two pharmacokinetic drug interaction studies in healthy subjects. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 543].

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Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction

Kearney et al. conducted an open-label, multidose, one-sequence, drug-drug interaction study with 28 healthy male or female subjects. This study compared ddl EC 250mg pharmacokinetics administered with TDF simultaneously (fasted or fed), or in a staggered fashion (2 hours after with food) to ddl EC 400mg alone (fasted).

Regimen	ddl AUC (hr·mcg/mL)	Geometric Mean Ratio (90% CI)
ddl EC 400mg alone	2.75	-
ddl EC 250mg + TDF
Staggered (2hr prior)	2.74	99.8 (89.2, 112)
Simultaneous +light meal	2.44	88.6 (76.8, 102)
Simultaneous fasted	3.14	114 (100, 131)

ddl EC 250mg staggered from TDF was bioequivalent to ddI EC 400mg given alone. Most Adverse events were mild to moderate in severity with one person experiencing grade 3 hostility, nausea and headache.

Reference
Kearney BP, Isaacson E, Sayre J, et al. Didanosine and Tenofovir DF Drug-drug interaction: Assessment of didanosine dose reduction. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 533].

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Lack of interaction between stavudine extended-release formulation and tenofovir disoproxil fumarate

Kaul et al conducted a single-center, open-label study with 18 healthy subjects to evaluate the pharmacokinetics of co-administration of extended-release stavudine (d4T XR) and tenofovir disoproxil fumarate (TDF). Subjects received a single 100mg oral dose of d4T XR with a light meal (373 kcal) on day 1, TDF 300mg once daily with a light meal from days 2-8 and a single d4T XR 100mg dose with TDF 300mg and a light meal on day 9. The following pharmacokinetic parameters were reported.

	dXT XR alone Geometric mean (coefficient of variation)	dXT XR + TDF Geometric mean (coefficient of variation)	Geometric mean ratioPoint estimates(90% CI)
Cmax (ng/mL)	274 (31%)	275 (26%)	1.01 (0.92, 1.10)
Tmax (h)*	5.0 (3.5, 6.0)	4.0 (3.5, 6.0)	--
AUC (h•ng/ml)	2682 (29%)	2765 (28%)	1.03 (0.97, 1.09)

* Median (minimum, maximum)

The d4T concentration-versus time profiles were super-imposable. dXT XR plus TDF was bioequivalent to dXT XR given alone. The most common adverse effects for treatment groups were nausea, body ache and fatigue. TDF did not affect the PK of d4T XR and a dose adjustment dose not appears to be necessary for d4T XR and TDF.

Reference
Kaul S, Bassi K, Damle B, et al. Lack of interaction between stavudine extended-release formulation and tenofovir disoproxil fumarate. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 534].

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Enfuvirtide: investigations on the drug interaction potential in HIV-infected patients

Boyd et al conducted an open-label, sequential, and cross-over study to compare the pharmacokinetics of enfuvirtide (ENF) in the presence of co-administered ritonavir (RTV) boosted saquinavir (SQV), RTV alone and rifampicin (rifampin). Each study included 12 HIV-1 infected patients who had received up to 3 NRTIs. In study 1 and 2, the subjects were either receiving ENF 90mg twice daily for 7 days with SQV (soft gel capsule) 1000mg twice daily plus RTV 100mg twice daily (SQV/r) on days 4-7 (study 1), or RTV 200mg twice daily (study 2) on days 4-7. Blood samples were collected on days 3-7. In study 3, subjects received ENF 90mg twice daily on days 1-3 and 11-13 and rifampicin (rifampin) 600mg daily from days 4-13. Blood samples were collected on days 3 and 13. Geometric mean ratios of AUC₁₂h for ENF were shown as follow.

Study	Geometric mean ratio of AUC12h (90% CI)
1	1.14 (1.05-1.24)
2	1.22 (1.08-1.37)
3	0.98 (0.89-1.06)

Study 1 and 3 showed bioequivalence and suggested that ENF PK was not affected by co-administration of SQV/r and rifampicin (rifampin). However, study 2 showed that RTV might have an effect on ENF. Further studies are needed to better define the effect of RTV on ENF. ENF was well tolerated in these three studies. Most adverse effects were mild and no serious adverse effect occurred during these studies.

Reference
Boyd M, Ruxrungtham K, Zhang X et al. Enfuvirtide: investigations on the drug interaction potential in Hive-infected patients. Presented at 10th Conference on Retrovirus and Opportunistic Infections; 2003 Feb 10 - Feb 14; Boston, MA. [abstract 541]

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