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Antimicrobial Agents and Chemotherapy, February 2004, p. 430-436, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.430-436.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Saquinavir plus Low-Dose Ritonavir in Human Immunodeficiency Virus-Infected Pregnant Women{dagger}

Edward P. Acosta,1* Arlene Bardeguez,2 Carmen D. Zorrilla,3 Russell Van Dyke,4 Michael D. Hughes,5 Sharon Huang,5 Lisa Pompeo,2 Alice M. Stek,6 Jane Pitt,7 D. Heather Watts,8 Elizabeth Smith,9 Eleanor Jiménez,10 Lynne Mofenson,8 and the Pediatric AIDS Clinical Trials Group 386 Protocol Team

University of Alabama at Birmingham, Birmingham, Alabama,1 University of Medicine and Dentistry of New Jersey, Newark, New Jersey,2 University of Puerto Rico,3 San Juan City Hospital, San Juan, Puerto Rico,10 Tulane University Medical School, New Orleans, Louisiana,4 Harvard School of Public Health, Boston, Massachusetts,5 University of Southern California, Los Angeles, California,6 Columbia University College, New York, New York,7 National Institute of Child Health and Human Development, Rockville,8 Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland9

Received 3 July 2003/ Returned for modification 18 September 2003/ Accepted 14 October 2003


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng · h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC12s) during gestation (29,373 ± 17,524 ng · h/ml [mean ± standard deviation]), during labor and delivery (26,189 ± 22,138 ng · h/ml), and during the postpartum period (35,376 ± 26,379 ng · h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC12, 7,811 and 13,127 ng · h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P <= 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It is well established that the pharmacokinetics of drugs may be altered during pregnancy (9, 10). Factors that may lead to pregnancy-induced changes in drug absorption and disposition include increased gastric and intestinal emptying times, reductions in the levels of gastric acid secretion, increases in the levels of mucus secretion, plasma volume expansion, increased cardiac output, changes in organ blood flow, stimulation of hepatic microsomal enzymes, and inhibition of microsomal oxidases. Many of these physiologic changes begin during the second trimester and become marked during the third trimester. These changes make prediction of the effect of pregnancy on the pharmacokinetics of drugs difficult.

Considerable data indicate that there is a significant association between antiretroviral drug concentrations and the virologic response or toxicity, particularly for the protease inhibitors (PIs) (1). These relationships signify that antiretroviral drug exposure, expressed as either the area under the curve (AUC) or the trough concentration (Cmin), should ideally be maintained above a defined threshold concentration throughout the entire course of treatment in order to prevent viral replication and the development of resistant isolates. As pregnancy can significantly alter the levels of drug exposure, it is critical to understand the effects of pregnancy on antiretroviral absorption and disposition in order to ensure that adequate concentrations are achieved in the plasma of women receiving these drugs to prevent the development of resistance and perinatal transmission. The purpose of this study was to evaluate the pharmacokinetics of the soft-gel capsule form of saquinavir (SQV) plus low-dose ritonavir (RTV) at a dose of 800/100 mg twice a day (b.i.d.) when administered to HIV-infected pregnant women during gestation, during labor and delivery, and at 6 weeks postpartum.

(This work was presented in part at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, Calif., 27 to 30 September 2002.)


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study design. This was a multicenter, phase I, AUC-targeted, formal pharmacokinetic evaluation of SQV plus low-dose RTV in HIV-infected pregnant women with singleton pregnancies at between 14 and 32 weeks of gestation. The nucleoside analogs lamivudine (3TC) plus zidovudine (ZDV) were administered concomitantly. The study was approved by the local institutional review boards of the institutions participating in the study, and all women gave signed informed consent. Stage I of this study evaluated SQV alone plus ZDV and 3TC. The results of the pharmacokinetic studies indicated that SQV alone did not produce adequate exposures in this population (2). Consequently, stage II of this protocol included a pharmacokinetic evaluation of SQV plus low-dose RTV in an attempt to overcome the low level of SQV exposure when it was administered as a single PI.

Women could enroll in the study if they had documented HIV infection, were pregnant and at 14 to 32 weeks of gestation, were age 13 years or older (or the age of consent of the local institutional review board, whichever was higher), and had a normal targeted fetal ultrasound. Women who had previously been treated with didanosine, stavudine, ZDV, or 3TC for less than 3 weeks were also eligible. Women who had previously been treated with SQV (with or without RTV) in combination with ZDV and 3TC for <3 weeks were eligible, as were those who had received this combination for >3 weeks and who had HIV RNA levels in plasma of <400 copies/ml before entry into the study. Primary exclusion criteria included receipt of nonnucleoside reverse transcriptase inhibitors in the 3 weeks prior to entry into the study, current substance abuse, an active opportunistic or serious bacterial infection at the time of entry, past or present obstetrical complications, or current significant medical disorders, including chronic malabsorption or diarrhea.

Treatment was orally administered antepartum at the following doses: SQV-RTV at 800/100 mg b.i.d., 3TC at 150 mg b.i.d., and ZDV at 200 mg three times a day (t.i.d.) (or ZDV at 300 mg and 3TC at 150 mg b.i.d. in a fixed-dose combination). During the intrapartum period, ZDV was administered according to the standard of care (2 mg/kg intravenously over 1 h, followed by administration at 1 mg/kg per h until the cord was clamped). 3TC and SQV-RTV (800/100 mg) were administered orally at the onset of active labor and were continued every 12 h. The four-drug regimen was continued for 12 weeks postpartum at the same doses used during the antepartum period.

Rationale for AUC-targeted dosing strategy. The SQV target exposure for an individual was defined as an AUC at 24 h (AUC24) >10,000 ng · h/ml. This target was based on the results of a study conducted with 31 nonpregnant HIV-infected adults (8), in which a significant relationship between the SQV AUC24 and a reduction in the HIV RNA level in plasma was observed. An average SQV AUC8 of 7,249 ng · h/ml was achieved with a dose of 1,200 mg t.i.d. The model-derived AUC24 required to produce 50% of the maximum treatment effect (AUC24 EC50) was 3,226 ng · h/ml. We chose 10,000 ng · h/ml as the minimum acceptable AUC24 for any individual participant receiving SQV-RTV at 800/100 mg b.i.d. because this level of exposure more closely approximates the estimated EC90. If the target AUC was not achieved by an individual subject after 2 weeks of therapy, the regimen was to be changed to the combination of SQV-RTV at 1,200/100 mg b.i.d. and the pharmacokinetic assessment was to be repeated. If the level of SQV exposure was still below the targeted AUC24, participants were to be withdrawn from the study and offered the best available treatment options.

Pharmacokinetic study design and analyses. Pharmacokinetic assessments were conducted after at least 2 weeks of treatment but at not later than 34 weeks of gestation, during labor and delivery, and at 6 weeks postpartum. Blood samples (5 ml) for quantitation of SQV and RTV levels in plasma were collected predosing and at 1, 2, 4, 6, 8, and 12 h postdosing following an observed ingestion of an oral dose. SQV and RTV concentrations were quantitated simultaneously by a previously described high-performance liquid chromatography with UV detection methodology (11). The lower limit of detection for both compounds was 50 ng/ml, with less than 10% intra- and inter-assay variabilities at the low and high ends of the quality control curve. Since food significantly increases the level of absorption of SQV, all participants consumed a standard, high-fat meal (1,000 kcal with 47 to 55 g of fat) at the time of the pharmacokinetic evaluations. A lighter meal consisting of Ensure or milk was administered during labor and delivery. For the neonates, plasma samples for the quantitation of SQV and RTV were scheduled for collection at birth and 1 and 3 h after birth, and a cord blood sample was obtained from each subject at delivery.

Standard noncompartmental techniques (WinNonlin Professional, version 3.2; Pharsight Corp., Mountain View, Calif.) were used to assess the pharmacokinetic parameters for SQV and RTV derived from each intensive pharmacokinetic evaluation at steady state. The AUC12 was determined by using the linear trapezoidal rule (6). The AUC24 was taken as twice the AUC12. The maximum concentration of blood in plasma (Cmax) and the time to Cmax (Tmax) were determined. Oral clearance (CL/F) was calculated as dose/AUC12. The terminal volume distribution (Vz/F) was calculated as the dose divided by the product of the elimination rate constant ({lambda}z) and AUC. The elimination half-life (t1/2) was determined by linear regression analysis of the terminal slope and the formula ln(2)/{lambda}z. Regression analysis was used to estimate the trough concentration at 12 h (C12) if the measured value was below the limit of quantitation (BLQ) of the assay, which was <50 ng/ml. The pharmacokinetic parameters derived during gestation, labor and delivery, and the postpartum period were compared (i.e., by comparison of the values of the parameters obtained during gestation and labor and delivery, during gestation and the postpartum period, and during labor and delivery and the postpartum period) for statistical significance by the nonparametric Wilcoxon signed rank test, with the level of significance set at 0.05. The geometric mean ratios (GMRs) of the pharmacokinetic parameters for SQV and RTV obtained postpartum/pharmacokinetic parameters for SQV and RTV obtained antepartum and the associated 95% confidence intervals (CIs) were also calculated.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient demographics. The baseline characteristics of the study participants are listed in Table 1. Thirteen women from four clinical sites were enrolled in the study and completed the pharmacokinetic evaluations during pregnancy. Two (15%) subjects were enrolled at the University of Puerto Rico, three (23%) each were enrolled at the City Hospital of San Juan and the Los Angeles County Medical Center, and five (38%) were enrolled at the University of Medicine and Dentistry of New Jersey. Pharmacokinetic data were available for 7 subjects during labor and delivery and 12 subjects during the postpartum period. Incomplete sample collections during labor and delivery were carried out for three subjects, so pharmacokinetic analyses could not be completed; and no samples were collected for three subjects. Of the three subjects in the last group, one had an elective delivery by cesarean section, one had a precipitous delivery, and one discontinued the study treatment prior to labor and delivery. Therefore, we were also unable to collect samples at the postpartum visit for the last subject. RTV concentration-time data for samples obtained during labor and delivery were not evaluable for two of seven subjects. For both of these subjects, a terminal elimination phase could not be estimated and it was not possible to calculate an AUC12; therefore, the data were not included. No measured C12 values were below the limit of quantitation of the assay.


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  		TABLE 1. Baseline characteristics of study participants

 
Pharmacokinetic study results. The results of the pharmacokinetic studies for SQV and RTV for each evaluation period are summarized in Tables 2 and 3, respectively. The AUC24 was not below the targeted exposure of 10,000 ng · h/ml (equivalent to an AUC12 of 5,000 ng · h/ml) for any of the subjects. The pharmacokinetics of both SQV and RTV exhibited considerable intersubject variability, as indicated by the high coefficients of variation for the parameters in Tables 2 and 3 and the scatterplots depicted in Fig. 1. Nevertheless, no significant differences in the pharmacokinetic parameters for SQV were noted when the values obtained during gestation, labor and delivery, and the postpartum period were compared. For RTV, however, the values of Cmax, C12, and AUC12 were significantly different between the gestational and postpartum visits. The RTV C12 during labor and delivery was also significantly different from that during the postpartum period (P = 0.043). In general, the results for both SQV and RTV demonstrate trends toward lower levels of drug exposure during gestation and labor and delivery compared with those during the postpartum period. This trend is highlighted by examination of the GMRs of the AUCs postpartum/AUCs antepartum and the 95% CIs for SQV and RTV. The GMR for the SQV AUC was 1.21, signifying a 21% increase in the level of SQV exposure postpartum. However, the 95% CI was 0.62 to 2.37, indicating that we cannot rule out a relative doubling or a one-third reduction of the AUC from the antepartum period to the postpartum period. The GMRs (95% CIs) for the Cmax, Tmax, and C12 values for SQV were 1.23 (0.61 to 2.49), 0.98 (0.59 to 1.65), and 1.22 (0.63 to 2.39), respectively. The GMRs (95% CIs) for the AUC, Cmax, Tmax, and C12 values for RTV were 1.57 (0.90 to 2.73), 1.69 (0.96 to 2.98), 0.85 (0.41 to 1.75), and 1.77 (1.05 to 2.98), respectively; these represent 57, 69, -15, and 77% changes in the values of these parameters from the antepartum period to the postpartum period, respectively.


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  		TABLE 2. Pharmacokinetics of SQV

 

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  		TABLE 3. Pharmacokinetics of RTV

 


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  		FIG. 1. SQV and RTV concentration-time curves for subjects receiving SQV at 800 mg b.i.d. in combination with RTV at 100 mg b.i.d. (A) Results for SQV during gestation (n = 13); (B) results for SQV during labor and delivery (n = 7); (C) results for SQV during the postpartum period (n = 12); (D) results for RTV during gestation (n = 13); (E) results for RTV during labor and delivery (n = 5); (F) results for RTV during the postpartum period (n = 12). The thick solid curve in each plot represents the median.

 
Blood samples were collected from 11 neonates for quantitation of SQV and RTV. The median weight of the neonates was 3.0 kg (range, 2.4 to 3.7 kg). The SQV concentrations were measurable in 6 of the 11 neonates, and RTV concentrations were measurable in only 1 of the 11 neonates. A total of 24 plasma samples were collected from the 11 neonates at birth following maternal SQV-RTV dosing. Three of the samples had insufficient volumes for drug quantitation. The levels of SQV in 8 of the remaining 21 (38%) samples and RTV in 19 of 21 (90%) samples were BLQ. Thus, SQV levels were measurable in a total of 13 samples and RTV levels were measurable in two samples. Following maternal dosing, plasma samples were scheduled to be collected from the neonates at birth and at 1 and 3 h after birth. Of the 11 neonates, samples were collected at all three time points from only 3 of them, and the samples were collected at various times following maternal dosing, so the results were grouped together to get an overall perspective of drug transfer across the placenta. The median time of plasma sample collection from the neonates after maternal dosing was 7.8 h (range, 2.8 to 11.1 h). The median concentration for the 13 samples with measurable SQV values was 141.2 ng/ml (range, 50.4 to 478 ng/ml). The RTV concentrations measurable in two samples were 77.5 and 110.2 ng/ml, respectively. Seven cord blood samples were also obtained. The SQV and RTV levels in three of seven cord samples were BLQ. The median time between maternal dosing during labor and cord blood collection was 6.1 h. The SQV concentrations in the four cord blood samples with measurable concentrations ranged from 128 to 357 ng/ml (median, 159 ng/ml). The RTV concentrations in the four cord blood samples with measurable concentrations ranged from 60 to 177 ng/ml (median, 137 ng/ml).


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
SQV-RTV at 800/100 mg b.i.d. in combination with ZDV and 3TC produced sufficient overall drug exposure in HIV-infected pregnant women. Previously published data suggest that SQV as a single PI produces inadequate systemic exposure in HIV-infected pregnant women (2). The previously published data suggest that SQV at 1,200 mg t.i.d. produces levels of systemic exposure (AUC8, C8) considerably below those observed in nonpregnant adult populations. As a result, Pediatric AIDS Clinical Trials Group Protocol 386 was amended to allow subsequent participants to begin therapy with SQV-RTV at 800/100 mg b.i.d. All participants receiving this regimen consistently demonstrated AUC24 values in excess of the target value (10,000 ng · h/ml) during gestation, during labor and delivery, and at 6 weeks postpartum. The results indicate that there were no significant differences in the pharmacokinetics of SQV among the three evaluation periods, but for RTV significant differences between the Cmax, C12, and AUC12 values obtained during gestation and those obtained during the postpartum period were noted. In general, the pharmacokinetic results for both SQV and RTV follow a trend consistent with pregnancy-induced changes in drug absorption and disposition. During gestation, the AUC, Cmax, and C12 values were all lower than those obtained during the postpartum period. The median concentration-time curves for SQV and RTV during the postpartum evaluation period were considerably higher than those during the other two evaluation periods (Fig. 2). Although the difference was not statistically significant, analysis of the GMRs and 95% CIs confirms this trend; the SQV and RTV AUCs during the postpartum period increased 21 and 57%, respectively. SQV concentrations were measurable in some plasma and cord blood samples from the neonates. These results suggest that elevated plasma SQV concentrations may increase the level of transfer of the drug across the placenta, but overall, very little SQV crossed the placenta and reached the blood of the infants.



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  		FIG. 2. Median SQV and RTV concentration-time curves for gestation (line with large dashes), labor and delivery (line with small dashes), and the postpartum period (solid line).

 
The pharmacokinetics of SQV and SQV in combination with low-dose RTV have been extensively evaluated in the nonpregnant adult population. The mean ± standard deviation AUC8, Cmin, and Cmax obtained with SQV at 1,200 mg t.i.d. are 7.2 ± 6.2 mg · h/liter, 0.11 ± 0.09 mg/liter, and 2.5 ± 1.9 mg/liter, respectively (S. Cox, B. Conway, W. Freimuth, E. Berber, L. Paxton, B. Carel, L. Nieto, C. Rivera, M. Wolff, J. Benetucci, P. Cahn, and K. Williams, Program Abstr. 7th Conf. Retrovir. Opportunist. Infect., abstr. 82, 2000; Fortovase [saquinavir] prescribing information, 1997; Roche Laboratories, Inc., Nutley, N.J.). The present study has been the only formal pharmacokinetic evaluation of SQV-RTV at 800/100 mg b.i.d.; however, our values for SQV and RTV appear to be higher than those reported previously (12) when the combination was given to nonpregnant patients at 1,000/100 mg b.i.d. For example, the median SQV AUC12, Cmax, and C12 at the postpartum visit in the present study were 30 mg · h/liter, 4.3 mg/liter, and 1.1 mg/liter, respectively. Previous data for nonpregnant adults show that the median values of the same parameters are approximately 23 mg · h/liter, 4 mg/liter, and 0.5 mg/liter, respectively (12). The median values of AUC12, Cmax, and C12 for RTV during the postpartum period in the present study were 12.5 mg · h/liter, 2.0 mg/liter, and 0.60 mg/liter, respectively, whereas previously (12) they were 7.0 mg · h/liter, 1.0 mg/liter, and 0.22 mg/liter, respectively. It is unclear why in the present study the SQV and RTV concentrations during the postpartum period were higher than those in nonpregnant adults. Since the physiologic changes of pregnancy usually return to the baseline by 6 weeks after birth, the populations in the two studies should be relatively similar. Interestingly, the 13 subjects in the present study were all women, whereas the subjects in the study of SQV-RTV at 1,000/100 mg b.i.d. (12) were all men (n = 6). Recent reports suggest that there are differences in the clearance of SQV between men and women (approximately 50% decrease in SQV clearance in women), which may explain why the level of SQV exposure (AUC12) during the postpartum period in this study is considerably higher than that in men detected previously (12; R. C. Brundage, E. P. Acosta, R. Haubrich, D. Katzenstein, R. Gulick, and C. V. Fletcher, Program Abstr. 9th Conf. Retrovir. Opportunist. Infect., abstr. 779-W, 2002; C. V. Fletcher, H. Jiang, R. C. Brundage, E. P. Acosta, R. Haubrich, D. Katzenstein, and R. Gulick, Abstr. 2nd Int. AIDS Soc. Conf. HIV Pathogenesis Treatment, abstr. 128, 2003).

The pharmacokinetics of nelfinavir (NFV) and indinavir (IDV), each in combination with ZDV and 3TC, have also been evaluated in HIV-infected women during pregnancy and at 6 weeks postpartum (Y. Bryson, A. Stek, M. Mirochnick, L. Mofenson, J. Connor, H. Watts, S. Huang, M. Hughes, B. Cunningham, L. Purdue, Y. Asfaw, and E. Smith, Program Abstr. 9th Conf. Retrovir. Opportunist. Infect., abstr. 795-W, 2002; D. Wara, R. Tuomala, Y. Bryson, M. Hughes, S. Huang, L. Mofenson, M. Culnane, J. Unadkat, and the Pediatric AIDS Clinical Trials Group, Abstr. 2nd Conf. Global Strategies Prevent. HIV Transmission Mothers to Infants, abstr. 447, 1999). Differences in the pharmacokinetics of these PIs were also observed during pregnancy. The initial NFV dosing regimen used (750 mg t.i.d.) resulted in inadequate NFV concentrations (defined as an AUC <15 mg · h/liter, which was the 10th percentile of the value for nonpregnant adults) in six of nine women studied. When NFV was administered at 1,250 mg b.i.d., NFV concentrations were still inadequate in 3 of the 16 women studied. Decreased levels of exposure to IDV during the antepartum period compared with those during the postpartum period have also been reported in pregnant women; the median IDV AUC8 was 63% lower and the median C8 was 83% lower during the antepartum period compared with the values obtained during the postpartum period, with significant variability in the concentrations in plasma. These data and the results of our study underscore the importance of evaluating the pharmacokinetics of antiretroviral agents in HIV-infected pregnant women. Collectively, these studies suggest that there is a significant disparity in the pharmacokinetics of PIs in HIV-infected pregnant women compared with those in nonpregnant adult individuals. These differences may require alterations of the drug dosage or the frequency of administration or may require the coadministration of another agent to enhance PI concentrations (such as low-dose RTV coadministration with SQV) during pregnancy.

Many women treated for HIV infection receive therapy for a limited time antepartum but continue treatment during the postpartum period. It is unclear how long a patient can be expose to subtherapeutic SQV concentrations before clinically significant drug resistance develops. This is an important point with respect to PIs because of the known concentration-response relationships. Pharmacodynamic data are critical in antiretroviral therapy. Concentration-effect relationships have been demonstrated for PIs in particular, and the levels of systemic exposure to PIs fluctuate widely among patients, as evidenced by the results of the present study. The underlying purpose of establishing concentration-effect relationships is to identify the minimum level of drug exposure required to produce a maximum decrease in viral replication while preventing unwarranted toxicities. It has been shown that the AUC24 EC50 for monotherapy SQV is 3,225 ng · h/ml (8). The estimated EC90 (which more closely approximates the maximum effect that a drug can achieve) is approximately 10,000 ng · h/ml (in general, the EC90 is approximately three to four times the EC50, depending on the shape of the concentration-response relationship). Therefore, we believe that our targeted AUC24 exposure level of 10,000 ng · h/ml is an appropriate threshold for evaluation of the adequacy of this regimen.

The results of this study suggest that the pharmacokinetics of SQV when it is used with low-dose RTV at 800/100 mg b.i.d. produces levels of drug exposure in HIV-infected pregnant women sufficient to suppress the replication of SQV-sensitive virus. The AUCs were well in excess of the targeted value in all subjects. In addition, the C12s were also above a suggested acceptable lower limit of 50 ng/ml, based on prior pharmacodynamic analyses (7), and were within or above the range of 100 to 250 ng/ml established by a consensus panel (3). Our pharmacokinetic results suggest that the level of SQV exposure during the postpartum period is increased relative to that in nonpregnant individuals (12). These higher levels of exposure may be the result of differential SQV metabolism between the sexes, because SQV clearance has been shown to be almost halved in women. Several pharmacokinetic parameters for RTV were significantly different between the gestation and the postpartum periods, however. This finding suggests that induction of the multidrug resistance 1 gene-dependent protein product, p glycoprotein (P-gp), may play a role in RTV absorption and/or disposition during pregnancy. P-gp is a bidirectional cellular countertransport system that plays an important role in determining PI concentrations because it can mediate the efflux of PIs from cells (5). RTV has been shown to be a substrate for P-gp (13), and the human placenta expresses P-gp throughout pregnancy (4). The results of this study suggest that a pregnancy-induced modulation of P-gp may be responsible for the differences in the pharmacokinetics of RTV that were observed, but this will need to be evaluated further. The lack of differences in the values of the pharmacokinetic parameters for SQV may have been masked by the extreme inter- and intrasubject variabilities in plasma SQV concentrations.

In conclusion, this is the first formal pharmacokinetic evaluation of a dual PI regimen in HIV-infected pregnant women during gestation, labor and delivery, and the postpartum period. Pharmacokinetic results indicate that the plasma SQV concentrations are in excess of the pharmacodynamically derived AUC target when SQV is administered with low-dose RTV at 800/100 mg b.i.d. The pharmacokinetic parameters for RTV were different between the gestation and the postpartum periods, indicating that pregnancy induces considerable alterations in the levels of absorption of RTV and its disposition. This SQV-RTV regimen produced adequate pharmacokinetics and should be considered a viable treatment option for pregnant women pending the results of tests of its long-term clinical safety and tolerability.


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   ACKNOWLEDGMENTS
 
We are indebted to the patients who participated in this trial, Michele Turner for performing the SQV and RTV assays, and Jennifer R. King for aid with pharmacokinetic analyses and manuscript preparation. We also thank George McSherry, Jocelyn Grandchamp, and Rodrigo Díaz-Velazco for their contributions to subject enrollment and Shiara Ortiz-Pujols for her outstanding role as our clinical trials specialist.

This study was supported by grant UO1-AI41089 from the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.


   FOOTNOTES
 
* Corresponding author. Mailing address: Division of Clinical Pharmacology, University of Alabama at Birmingham School of Medicine, 1530 3rd Ave. South, VH 116, Birmingham, AL 35294-0019. Phone: (205) 934-2655. Fax: (205) 934-6201. E-mail: EAcosta{at}uab.edu. Back

{dagger} This report is dedicated in the memory of Jane Pitt, whose clinical and scientific contributions to this field will always be remembered. Back


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Antimicrobial Agents and Chemotherapy, February 2004, p. 430-436, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.430-436.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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