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First Dose and Steady-state Genital Tract Pharmacokinetics of Ten Antiretroviral Drugs in HIV-infected Women: Implications for Pre- and Post- Exposure Prophylaxis
Julie Dumond*, R Yeh, K Patterson, A Corbett, B H Jung, N Rezk, A Bridges, E Dempsey, M Cohen, and A Kashuba
Univ of North Carolina at Chapel Hill, US
Background: Antiretroviral
(ARV) therapy has been shown to reduce GT HIV RNA and potentially decrease the
risk of sexual transmission. ARVs rapidly
achieving high GT concentrations (CONC) may be targets for optimal PREP and PEP. To assist in choosing the most appropriate
regimens, this investigation comprehensively evaluated first dose and SS PK of 10 ARVs in
the female GT (FGT).
Methods: A
non-blinded, PK study was performed in 23 HIV-infected women initiating
provider-selected ARVs including combinations of the following: lamivudine
(3TC), zidovudine (ZDV), abacavir (ABC), emtricitibine (FTC), didanosine (ddI),
stavudine (d4T), efavirenz (EFV), lopinavir (LPV), ritonavir (RTV), and
atazanavir (ATV). Six paired blood
plasma (BP) and directly aspirated GT samples were obtained over a dosing
interval around observed doses on Day 1 (D1) and after Day 21 (SS). BP and GT CONC were measured by validated
LC/UV and LC/MS/MS assays. Data were
analyzed by noncompartmental PK and nonparametric statistical methods. GT:BP
AUC ratios were calculated and are presented as median (IQR).
Results:
|
Drug*
|
AUC Ratio D1
|
AUC Ratio SS
|
Drug*
|
AUC Ratio D1
|
AUC Ratio SS
|
|
ZDV
|
3.7 (0.9, 10.1)
|
2.3 (1.2, 21.2)
|
ABC
|
0.4 (0.1, 2.0)
|
<0.1 (<0.1, 0.1)
|
|
3TC
|
2.7 (1.1, 19.0)
|
4.4 (2.3, 6.4)
|
EFV
|
<0.1 (<0.1, <0.1)
|
<0.1 (<0.1, <0.1)
|
|
FTC
|
6.1 (1.3, 11.0)
|
6.7 (6.7, 6.7)
|
LPV
|
0.3 (<0.1, 1.0)
|
0.1 (<0.1, 2.4)
|
|
ddI
|
1.3 (<0.1, 2.4)
|
0.4 (0.4, 0.4)
|
RTV
|
0.2 (0, 0.4)
|
1.2 (0.2, 3.1)
|
|
d4T
|
<0.1 (<0.1, 0.5)
|
<0.1 (0, 0.1)
|
ATV
|
0.3 (0.1, 1.2)
|
0.7 (0.1, 1.9)
|
*data from 5.5 (4.3, 9) women
per drug were used to calculate ratios
At D1 and SS, ZDV, 3TC, and
FTC FGT exposures were higher than BP (p<0.02); d4T, RTV, EFV, LPV, and ATV
GT exposures were less than BP (p<0.03).
A trend towards higher FGT exposures on D1 compared to SS was noted for
ZDV, ABC, and ddI (p=NS).
Conclusions:
Understanding exposure profiles for ARVs in the GT is particularly important
for PREP, PEP, and possibly the prevention of mother-to-child-transmission.
ZDV, 3TC, and FTC achieve GT exposures greater than that of BP. Since standard
BP CONC for these agents have demonstrated virologic efficacy, it would be
expected that the higher GT CONC would make these excellent candidates for
PREP/PEP regimens. ATV and ddI achieve moderate GT CONC and may also prove
useful in these regimens (ATV in particular with a low IC50 for HIVWT).
ARVs achieving <10% of BP exposure in the GT (d4T, LPV, EFV) may be less
optimal candidates.
|
