Other selected PK and drug interaction summaries from EACS
This report summarises drug interaction and pharmacology studies presented at this recent meeting. Unless stated otherwise, all references are to the 12th European AIDS Conference (EACS), 11-14 November 2009, Cologne.
Raltegravir and famotidine or omeprazole
The effect of famotidine (20 mg single dose 2 h before raltegravir) or omeprazole (20 mg once-daily for 5 days, 2 h before raltegravir) was studied in 18 HIV-positive subjects stable on raltegravir (400 mg twice-daily) regimens. Coadministration of famotidine increased raltegravir AUC, Cmax and Ctrough by 45%, 60% and 6% respectively. Omeprazole increased raltegravir AUC, Cmax and Ctrough by 39%, 51% and 24%, respectively. The increases were not clinically significant and raltegravir may be coadministered with famotidine or omeprazole without dose adjustment.
This effect is less than previously seen in healthy volunteers.
Ref: Rhame F et al. Effects of famotidine and omeprazole on raltegravir pharmacokinetics in HIV-infected persons. 12th EACS, 11-14 November 2009,
Cologne. Abstract PE4.1/1.
P450 and P-gp activities in HIV-positive and HIV-negative subjects
The activity of CYP3A, 2D6 and P-gp were investigated in 30 HIV positive, treatment naive patients and 12 HIV-negative controls. Subjects were given a phenotyping cocktail containing midazolam (1.5mg, intestinal and hepatic CYP3A), dextromethorphan (30 mg, CYP2D6), digoxin (0.5 mg, P-gp) and IV midazolam (1.0mg, hepatic CYP3A).
The activities of CYP3A, CYP2D6 and P-gp were lower in the HIV-positive subjects, but with the exception of CYP3A, the differences were small. Total CYP3A activity was 0.493-fold lower in HIV-positive subjects than in HIV-negative controls.
Within group variability was greater than between group variability, making it unlikely that dose adaptations based on infection status would be useful.
Ref: Jetter A et al. Are there differences between healthy volunteers and HIV-infected patients in the activities of CYP3A, CYP2D6 and P-glycoprotein. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.1/9.
MVC and CYP450 inhibitors or inducers
Maraviroc trough concentrations were determined in HIV positive subjects receiving maraviroc in combination with CYP450 inhibitors or inducers.
Median maraviroc trough concentrations were 83 ng/mL, with 24% being below target (50 ng/mL) in subjects receiving maraviroc 150 mg twice daily with a boosted PI (not TPV or APV). In subjects receiving maraviroc 300 mg twice daily with a boosted PI, the median trough concentration was 264 ng/ml and 9% were below target.
When maraviroc was administered as 300 mg twice daily without a boosted PI or NNRTI, median trough concentrations were 47 ng/mL and 55% were below target. Coadministration of maraviroc 600 mg twice daily with etravirine resulted in median trough concentrations of 77 ng/mL, of which 19% were below target.
There is data suggesting that the average concentrations (Cavg) may be a better parameter to correlate with viral response.
Ref: Sari-Chaaf Zet al. Maraviroc boosted (or not) by ritonavir? Pharmacokinetic results from routine therapeutic drug monitoring. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.2/1.
Abacavir and darunavir/r or raltegravir
This study investigated the steady-state plasma pharmacokinetics of abacavir (600 mg once daily) when co-administered with darunavir/ritonavir (900/100 mg once daily) or raltegravir (400 mg twice daily) to 19 HIV positive subjects.
Abacavir AUC, Cmax and Cmin decreased by 27%, 22% and 38%, respectively in the presence of darunavir/ritonavir. When coadministered with raltegravir, the AUC and Cmax of abacavir increased by 3% and 6%, respectively; Cmin decreased by 17%. It is important to relate the change in plasma abacavir exposure to the active intracellular carbovir triphosphate and a study is in progress.
Ref: Jackson A et al. Pharmacokinetics (PK) of plasma abacavir (ABC) in the absence and in the presence of darunavir/ritonavir (DRV/r) or raltegravir (RAL) in HIV-infected subjects. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.3/2.
TMC278 and oral contraceptives
The pharmacokinetic interaction between TMC278 (25mg once daily) and an oral contraceptive containing norethindrone/ethinylestradiol (1/0.035mg) was studied in 18 HIV negative females. Norethindrone pharmacokinetics were unaffected by TMC278 (11% decrease in AUC, 6% decrease in Cmax, 1% decrease in Cmin).
There was no statistically significant change in ethinylestradiol AUC (14% increase) or Cmin (9% increase), but Cmax increased by 17%, however, this is not expected to be clinically significant. Pharmacokinetics of TMC278 were within the expected range. There was no marked effect on FSH, LH and progesterone serum levels.
TMC278 and oral contraceptives containing norethindrone/ethinylestradiol can be coadministered without dose modifications.
Ref: Crauwels H et al. Pharmacokinetic interaction study between TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), and the contraceptives norethindrone plus ethinylestradiol. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.3/3.
Darunavir and raltegravir interaction
Darunavir trough concentrations were determined in 117 samples from 55 HIV-positive patients receiving darunavir containing regimens with either a NRTI or raltegravir.
Mean (± sd) darunavir concentrations were higher in the NRTI subjects than in the raltegravir subjects (4.20 ± 2.35 vs 2.63 ± 84 mg/L). However, the proportion of subjects with undetectable viral loads (<50 copies/mL) was higher in the raltegravir group than in the NRTI group.
After adjusting for time from last drug intake and concomitant drugs, a multivariate linear regression model confirmed raltegravir to be independently related to lower darunavir concentrations.
The mechanism of this unexpected interaction remains to be determined, but it does not appear to be virologically significant.
This data is consistent with a previous report from Garvey et al presentated at the IAS meeting in Cape Town (IAS 2009, LBPEB08). The absolute darunavir concentrations in the Fabbiani study are higher than previously reported.
Ref: Fabbiani M et al. Unexpected drug interaction between darunavir and raltegravir. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.3/4.
Raltegravir and unboosted atazanavir
The steady state pharmacokinetics of raltegravir (400 mg twice daily) and unboosted atazanavir (300 mg twice daily) were determined in 22 HIV-positive subjects who switched from their current regimen.
Atazanavir geometric mean AUC, Cmax and Ctrough were 14454 ng.h/ml, 2275 ng/ml and 419 ng/mL respectively. Raltegravir geometric mean AUC, Cmax and Ctrough were 7112 ng.h/ml, 1680 ng/mL and 62 ng/mL. Three subjects (14%) had atazanavir trough concentrations below 100 ng/mL.
At the time of switch, 79% subjects had undetectable viral load, but at week 24, all subjects had undetectable viral loads.
These data are generally consistent with Zhu et al (CROI 2009, abstract 696).
Ref: Ripamonti D et al. Steady-state pharmacokinetics, efficacy, safety and tolerability of dual regimen with atazanavir (300mg bid) plus raltegravir (400mg bid) in HIV-1-infected patients: 24-week results (CARDS study). 12th EACS, 11-14 November 2009, Cologne. Abstract LBPE4.3/5.
Nevirapine and efavirenz concentrations, during and after stopping rifampicin
Concentrations (12 h post dose) of nevirapine (400 mg/day, n=71) and efavirenz (600 mg/day, n=71) were determined at 6 and 12 weeks after starting rifampicin and then after rifampicin had been discontinued. Mean ±SD concentrations for nevirapine at weeks 6, 12 and after discontinuation were 5.6 ± 3.6, 5.5 ± 2.6 and 6.7 ± 3.5 mg/L, respectively.
Efavirenz concentrations at the same time points were 4.5 ± 4.3, 3.8 ± 3.5 and 3.5 ± 2.7 mg/L, respectively. Patients on efavirenz showed greater inter-patient variability whilst receiving rifampicin than patients on nevirapine.
Ref: Manosuthi W et al. Serial monitoring of drug concentrations while on and off rifampicin between standard doses of nevirapine-based and efavirenz-based antiretroviral regimens. 12th EACS, 11-14 November 2009, Cologne. Abstract PE4.6/1.
Traditional medicine use in Uganda
The use of African herbal medicines in HIV-positive subjects receiving antiretroviral therapy was assessed in four districts of Uganda by interviewing traditional medicine practitioners (n=25) and HIV-positive subjects (n=44).
Over 100 plant species were identified, with approximately 80% of preparations being taken orally.
Multi-plant preparations were common in 75% districts, with mono-plant preparations being predominant in one district. Plant parts frequently used were leaves (33%), stem bark (23%) and root bark (18%). The priority plants identified included Aloe sp, Erythina abyssinica, Sarcocephalus latifolius, Psorospermum febrifugum, Mangifera indica, Warburgia salutaris and Albizia coriaria.
The widespread use of traditional medicines with largely unknown effects on drug disposition indicates the need for studies in this area.
Ref: Lamorde M et al. Traditional medicine practices in the context of HIV in Uganda. 12th EACS, 11-14 November 2009, Cologne. Abstract PE19.9/1.