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Microsoft powerpoint - 08-243_sevinsky_icaac_poster.ppt

Effect of Efavirenz on the Pharmacokinetics of
Ethinyl Estradiol and Norgestimate in Healthy Female Subjects
H. Sevinsky, T. Eley, B. He, A. Persson, D. Garner, C. Yones, R. Nettles, R. Bertz and J. Zhang
Bristol-Myers Squibb Research and Development, Princeton, NJ USA Introducti
Introducti on
Results (Cont’d)
Results (Cont’d)
Results (Cont’d)
„ Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that is used in Pharmacokinetics
Table 1. Statistical Analyses for EE PK Parameters
the treatment of HIV-1 infection. It is an inducer of CYP3A4 and uridine-diphosphate Table 3. Statistical Analyses for LNG PK Parameters
glucuronosyl transferases (UGTs) in vivo.1,2,3 EFV is a Pregnancy Category D drug. „ Serial blood samples were collected up to 24 hours post-dose on Days 14, 42 and 70 for EE PK analysis, Days 42 and 70 for NGMN PK analysis and on Day 70 for EFV PK Adjusted Geometric Means
GMR (90% CI)
Table 5. Safety Results
Preventing pregnancy is critical in women receiving EFV as part of their antiretroviral Treatment (EE Dose)
Adjusted Geometric Means
GMR (90% CI)
Treatment
– Non-compartmental analysis using the validated program Kinetica™: Ortho Tri-
Treatment
„ Oral contraceptives (OC) containing an estrogen (ethinyl estradiol, EE) and a progestin are Cyclen LO
Ortho Cyclen +
among the most frequently used methods of birth control „ EE, NGMN and EFV Cmax, Tmax, AUC(TAU) and Cmin (concentration 24 hours post- EFV / Ortho
Ortho Tri-
(0.025 mg)
(0.035 mg)
(0.035 mg)
EFV / Ortho
Tri-Cyclen
Ortho Cyclen
Ortho Cyclen + EFV
EFV / Ortho
Cyclen LO
„ In a previous study, EFV 400 mg increased the single dose EE Cmax and AUC by 5% and Parameter
PK Parameter
0.20 (0.17, 0.23)
„ EE is metabolized by sulfotransferases (SULTs), CYP3A4 and UGTs.4 The specific – EE: standard curve from 10 - 500 pg/mL, QC deviations within ± 1.6% (0.95, 1.19)
enzymes involved in progestin metabolism have not been well-defined; however CYP3A4 – NGMN: standard curve from 99.5 - 4975 pg/mL, QC deviations within ± 2.5% AUC(TAU)
5,6 Exposure to OC components could potentially be impacted AUC(TAU)
– EFV: standard curve from 10 - 10,000 ng/mL, QC deviations within ± 11.2% (pgh/mL)
(0.80, 1.01)
0.17 (0.13, 0.21)
Most Frequent AEs - N(%) of subjects
(pgh/mL)
– LNG: standard curve from 100 - 10,000 pg/mL, QC deviations within ± 0.5% (0.75, 1.14)
„ The US Prescribing Information for Sustiva includes the fol owing information and recommendation: The potential interaction of EFV with OCs has not been ful y Pharmacodynamics
0.14 (0.10, 0.20)
characterized. A reliable method of barrier contraception should be used in addition to oral * comparisons are 0.035 mg EE + EFV relative to 0.025 mg EE in the absence of EFV „ Serum progesterone levels were determined at Day -2 and during each treatment (Study AEs: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe Day 18, 46 and 74) as a biomarker for possible ovulation „ EFV does not impact EE exposures when co-administered with Ortho Cyclen „ One (1) SAE of suicide attempt was reported during the post-treatment follow-up period, „ Progesterone is an endogenous hormone that peaks 5 - 9 days after ovulation; in women Statistics
B = Ortho Cyclen, C = Ortho Cyclen + EFV 600 mg considered probably related to study drug. Subject had a history of prior psychiatric taking OCs, ovulation is suppressed and progesterone levels typically remain below Progestins
hospitalization and medication for depression, not disclosed at screening „ The effect of EFV on the PK of EE, NGMN and LNG were assessed by point estimates and „ Most AEs were mild to moderate in intensity. Three (3) severe AEs in 3 subjects 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for EE, NGMN, and Figure 3. Mean Plasma Concentration versus Time Profiles for NGMN
„ NGMN and LNG exposures were markedly decreased in the presence of EFV (headache, anhedonia and severe depressed mood) were reported and considered „ This study was conducted in order to provide a better understanding of the interaction LNG Cmax, AUC(TAU) and Cmin, derived using general linear models on log-transformed EE 0.035 mg + NGM 0.25 mg QHS + EFV 600 mg QHS (N = 21) „ One (1) subject had AST and ALT laboratory abnormalities that were AEs and considered „ Differences in endogenous progesterone levels between treatments and their Objectives
Objectives
corresponding 95% CIs were estimated. These estimates were constructed using general Efavirenz
Figure 5. Scatter Plot of EFV AUC(TAU): Administered Alone in Women
Discussion
Discussion
Primary:
(historical data) and Coadministered with Ortho Cyclen „ In a previous study that resulted in increased single dose EE exposures when „ To determine the effect of coadministration of EFV 600 mg on the pharmacokinetics (PK) administered with EFV 400 mg, EFV was administered for only 7 days. The ability of of EE and norelgestromin (NGMN), an active metabolite of the progestin norgestimate EFV to induce CYP3A4 may not have been fully observed Demographics
Secondary:
„ In the current study, EFV 600 mg was dosed for 14 days with no observed impact on „ 28 women were enrol ed and treated, 19 subjects completed the study EE PK. The effect of EFV on EE PK potentially involves inhibition/induction of „ To characterize the PK of EFV when coadministered with the OC Ortho Cyclen® multiple metabolic pathways, resulting in no net change in EE exposure „ To assess the effect of EFV coadministered with Ortho Cyclen on serum progesterone „ Decreases in NGMN and LNG exposures are potentially due to induction of CYP3A4 – 2 due to poor adherence, 1 due to positive drug screen, 5 withdrew consent „ To assess the safety of EFV coadministered with Ortho Cyclen „ Mean age (range): 28 years (18 - 42 years) „ Progesterone levels remained suppressed (<10 ng/mL) when EFV was „ An exploratory analysis of the PK of levonorgestrel (LNG), an active metabolite of NGMN Table 2. Statistical Analyses for NGMN PK Parameters
coadministered with OCs; however these levels were assessed at a single time point and an active component of some OCs, was conducted in a subset of 6 subjects within the cycle and should be interpreted with caution „ 68% were White, 21% were Black, 4% were native Hawaiian/Pacific Islander Adjusted Geometric Means
GMR (90% CI)
Treatment
Ortho Cyclen +
EFV 600 mg
EFV 600 mg
Ortho Cyclen
Ortho Cyclen + EFV
EFV / Ortho
QD (historical
QD + Ortho
PK Parameter
0.54 (0.48, 0.61)
„ EFV exposures after coadministration with Ortho Cyclen are comparable to EFV „ EFV does not alter EE exposure when coadministered with Ortho Cyclen Study Design
Pharmacokinetics
Ethinyl Estradiol
AUC(TAU)
„ EFV significantly reduces exposure to NGMN and LNG when coadministered with „ Open-label, 3-period, 4-treatment single sequence study in healthy female subjects who 0.36 (0.33, 0.38)
(pgh/mL)
had been receiving a stable regimen of OC for at least 2 months Figure 2. Mean (SD) plasma concentration versus time profiles for EE
0.18 (0.15, 0.21)
„ EFV exposures after coadministration of Ortho Cyclen with EFV are comparable to Figure 1. Study Design
Pharmacodynamics
historical data in women when EFV 600 mg is administered alone EE 0.035 mg + NGM 0.25 mg QHS + EFV 600 mg QHS (N = 21) Table 4. Statistical Analyses for Progesterone Levels
„ AEs reported with Ortho Cyclen + EFV are not unexpected and consistent with those Days 1-28
Days 29-56
Days 57-77
Adjusted
Difference in Adjusted Means
„ These results reinforce the need for reliable methods of barrier contraception when Figure 4. Mean Plasma Concentration versus Time Profiles for LNG
Treatment
Mean (ng/dL)
Difference
Point Estimates (90% CI)
Treatment C
A: Ortho Tri-Cyclen
Treatment A
Treatment B
EE 0.035 mg + NGM 0.25 mg QHS + EFV 600 mg QHS (N = 6) B: Ortho Cyclen
Treatment D
References
References
D: Ortho Cyclen (3
days after EFV coad.)
1. Sustiva® (efavirenz) capsule and tablets. US prescribing information. Bristol-Myers Squibb Co., Princeton, NJ 2008.
In-house:
In-house:
In-house:
A = Ortho Tri-Cyclen LO (day 18), B = Ortho Cyclen (day 46), D = Ortho Cyclen (day 74, 3 Days 13-15
Days 41-43 and 56
Days 57-77
days after completing Ortho Cyclen + EFV) 2. Isentress™ (raltegravir) tablets. US prescribing information. Merck and Co., Inc. Whitehouse Station, NJ, 2008.
„ Single time point progesterone levels after coadministration of Ortho Cyclen and EFV 600 3. Noxafil® (posaconazole) oral suspension. US prescribing information. Ortho Tri-Cyclen LO: Phase I = 0.025 mg EE + 0.18 mg NGM, Phase II = 0.025 mg
mg are similar to those after administration of Ortho Cyclen alone.
Schering-Plough, Kenilworth, NJ, 2008.
EE + 0.215 mg NGM, Phase III = 0.025 mg EE + 0.25 mg NGM „ All subjects’ progesterone levels col ected at a single time point during 1 cycle on EFV + 4. Doose DR, Wang SS, Padmanabhan M, et al. Epilepsia 2003; 44(4): 540 - 549.
Ortho Cyclen: 0.025 mg EE + 0.25 mg NGM
Ortho-Cyclen were less than 125 ng/dL, below the 1000 ng/dL indicative of ovulation 5. Hammomd GL, Abrams LS, Creasy GW, et al. Contraception 2003; 67(2): 93 - 99.
„ Follow up visits were conducted on Day 85 ± 2 days and Day 108 ± 2 days for pregnancy Note: mean profile for Treatment A (Ortho Tri-Cyclen LO) is not shown 6. Kuhn W, Blode H and Mahler M. Contraception 1994; 49: 225 - 263.
testing and adverse event (AE) fol ow up.
48th Annual ICAAC/IDSA 46th Annual Meeting, October 25-28, 2008, Washington, DC

Source: http://www.hivandhepatitis.com/2008icr/aasld/posters/bms_Sevinsky.pdf

Microsoft word - korrekte entwurmung des pferdes.doc

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