43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Drug Interactions Between Caspofungin and Nelfinavir or Rifampin
JA Stone, E Migoya, L Hickey, P Deutsch, G Winchell, A Freeman, S Bi, R Desai, S Dilzer, K Lasseter, W Kraft, H Greenberg, S Waldman

Stone et al performed two placebo-controlled, randomized studies to evaluate the potential drug interaction between caspofungin (Cancidas™) when combined with nelfinavir (NFV) or rifampin (RIF). In the first study, healthy subjects received 1) caspofungin (CAS) 50mg IV QD alone (n=10), 2) CAS with NFV 1250mg BID (n=9), or 3) CAS with RIF 600mg QD (n=10). Healthy subjects in the second study received either 1) RIF 600mg QD for 28 days and CAS 50mg IV QD for the last 14 days (n=14), or 2) CAS 50mg IV QD alone for 14 days (n=12). The geometric mean ratio (GMR) (90% CI) for CAS AUC_0-24h when administered alone compared to the combined treatment groups is listed in the table below.

The CAS plasma trough value (C_24h) decreased by 14%-31% when co-administered with RIF. The RIF AUC_0-24h geometric mean ratio was 1.07 (0.83-1.38) when co-administered with CAS compared to administration of RIF alone. The authors concluded that the CAS did not influence nor was it influenced by the administration of NFV or RIF. However, RIF decreased the C_24h of CAS for which the authors suggested that the CAS dose be increased to 70mg when given concomitantly with RIF to achieve desired CAS levels.

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Effect of High-Dose Vitamin C (Vit C) on the Steady-State Pharmacokinetics (PK) of the Protease Inhibitor (PI) Indinavir (IDV) in Healthy Volunteers
D Slain, JR Amsden, RA Khakoo, MA Fisher, D Lalka, GR Hobbs

Vit C has been shown to induce P-450 enzymes, including CYP3A enzymes by which most PIs are metabolized. Slain et al performed a two-period, longitudinal study on the effects of 1 gram of Vit C per day on the plasma concentrations of the PI indinavir (IDV) in 7 healthy volunteers. The volunteers were given IDV 800mg every 8 hours for 4 doses (steady-state) both before and after receiving 1 gram of Vit C. Both IDV C_max (-20%, p = 0.04) and AUC_8hr (-14%, p < 0.05) were significantly decreased when co-administered with Vit C. IDV C_min decreased 32% (265 vs. 181ng/mL, p = 0.09) but did not reach statistical significance. Apparent oral clearance trended towards increasing in the presence of Vit C (0.438 vs. 0.525 L/kg/hr, p = 0.06). Half-life decreased slightly from 1.13 to 1.02 hrs (p = 0.12). The authors concluded that Vit C significantly decreases IDV plasma concentrations. Clinicians should caution patients about the use of Vit C with protease inhibitors, however, the decrease may not be clinically significant and more study is needed to see if these results are similar in the presence of RTV.

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Effect of Omeprazole (OMP) on the Plasma Concentrations of Indinavir (IDV) in HIV-Negative Subjects
JC Rublein, BJ Donovan, SB Hollowell, SS Min, D Theodore, RH Raasch, ADM Kashuba

Reports have stated that increasing gastric pH may decrease the absorption of IDV. Rublein et al performed a randomized, placebo-controlled, double-blind, crossover study on the potential drug interaction between omeprazole (OMP) and indinavir (IDV) in 14 HIV-negative subjects. Subjects received 7 days each of placebo, OMP 20mg, or OMP 40mg followed by either IDV 800mg or IDV 800mg/ritonavir (RTV) 200mg (OMP 40mg only) starting on day 7. A 7-day washout period occurred between each cycle. With the co-administration of OMP 40mg, mean IDV AUC₂₄ levels decreased by 46.7% (30mg x hr/L [95% CI: 21.9 to 41.1] versus 16mg x hr/L [11.8 to 21.7], p = 0.001). Mean IDV C₁₂ levels decreased by 55% (82.3ng/mL to 37.0ng/mL, p > 0.05). When RTV was combined with OMP and IDV, the IDV AUC₂₄ levels increased by 55% (30mg x hr/L [95% CI: 21.9 to 41.1] vs. 46.6mg x hr/L [95% CI: 34.0 to 63.8], p = 0.02) and these levels were similar to those achieved without OMP co-administration. The authors concluded that OMP significantly decreased IDV levels; however, when IDV was administered with RTV, IDV levels were increased by OMP.

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The Pharmacokinetics of Abacavir, a Purine Nucleoside Analog, are not Affected by Tenofovir DF
BP Kearney, E Isaacson, J Sayre, R Ebrahimi, AK Cheng

Kearney et al studied the potential PK interaction between abacavir (ABC) with tenofovir DF (TDF) in 8 healthy subjects. ABC plasma samples were collected over 24 hours when receiving ABC alone followed by co-administration of TDF with food for 13 days.

The ABC AUC_0-∞ and C_max increased 10% (range: 2.1% to 18%) and 12% (range: 1.3% to 26%), respectively, when administered with TDF. Mean TDF AUC_0-∞,ss and C_max,ss were 2690 ± 698ng x hr/mL and 276 ± 91.9ng/mL, respectively, when co-administered with ABC which the authors note as similar to historical controls. The authors concluded that TDF did not alter the PK of ABC.

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Tenofovir DF and Oral Contraceptives: Lack of a Pharmacokinetic Drug Interaction
BP Kearney, E Isaacson, J Sayre, AK Cheng

Kearney et al studied the potential PK interaction between tenofovir (TDF) and the oral contraceptive Ortho Tri-Cyclen® (norgestimate (NG)/ethinyl estradiol (EE)) in 20 healthy female subjects. Subjects were already taking the NG/EE oral contraceptive for a minimum of 3 months and were given TDF 300mg QD with food administered on days 23-29 of the study. Plasma samples of deacetyl norgestimate (the active metabolite of norgestimate - metabolized by CYP P450 enzymes) were drawn using 24 hour sampling on days 1 and 29 of the study.

Changes in oral contraceptive concentrations

Compound	AUC0-τ	Cmax
Deacetyl norgestimate	-5% (range: -9 to 1%)	-6% (range: -13 to 1%)
Ethinyl estradiol	-4% (range: -9 to 1%)	-6% (range: -12 to 0%)

Plasma levels of deacetyl norgestimate and ethinyl estradiol were similar regardless of TDF administration. Mean (± SD) TDF AUC_ss and C_max,ss co-administered with NG/EE was 2970 ± 744ng x hr/mL and 340 ± 85.2ng/mL, respectively, which was similar to previous data. The authors concluded that TDF did not alter the PK of deacetyl norgestimate or ethinyl estradiol.

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Compiled by Jeff Dearman.
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