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

ABSTRACT 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.

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Single-Dose Pharmacokinetics and Safety of Abacavir (1592U89), Zidovudine, and Lamivudine Administered Alone and in Combination in Adults with Human Immunodeficiency Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.7.1708 ◽

1999 ◽

Vol 43 (7) ◽

pp. 1708-1715 ◽

Cited By ~ 48

Author(s):

Laurene H. Wang ◽

Gregory E. Chittick ◽

James A. McDowell

Keyword(s):

Human Immunodeficiency Virus ◽

Adverse Events ◽

Nucleoside Analogs ◽

Neck Stiffness ◽

Time Curve ◽

Pharmacokinetic Interactions ◽

Immunodeficiency Virus ◽

The Mean ◽

Clinically Significant ◽

Hiv 1

ABSTRACT Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4+ cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5′-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (C max), the area under the concentration-time curve from time zero to infinity (AUC0–∞), time to C max(T max), and apparent elimination half-life (t 1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the meanC max of ZDV by approximately 20% (from 1.5 to 1.2 μg/ml), delayed the median T max for ZDV by 0.5 h, increased the mean AUC0–∞ for GZDV by up to 40% (from 11.8 to 16.5 μg · h/ml), and delayed the medianT max for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0–∞ for 3TC by approximately 15% (from 5.1 to 4.3 μg · h/ml), decreased the meanC max by approximately 35% (from 1.4 to 0.9 μg/ml), and delayed the median T max by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are relatively minor (for 3TC) and are therefore not considered to be clinically significant. No significant differences were found in the urinary recoveries of ZDV or GZDV when ZDV was coadministered with abacavir. There was no pharmacokinetic interaction between ZDV and 3TC. Mild to moderate headache, nausea, lymphadenopathy, hematuria, musculoskeletal chest pain, neck stiffness, and fever were the most common adverse events reported by those who received abacavir. Coadministration of ZDV or 3TC with abacavir did not alter this adverse event profile. The three-drug regimen was primarily associated with gastrointestinal events. In conclusion, no clinically significant pharmacokinetic interactions occurred between abacavir, ZDV, and 3TC in HIV-1-infected adults. Coadministration of abacavir with ZDV or 3TC produced mild changes in the absorption and possibly the urinary excretion characteristics of ZDV-GZDV and 3TC that were not considered to be clinically significant. Coadministration of abacavir with ZDV and/or 3TC was generally well tolerated and did not produce unexpected adverse events.

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Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.5.1694-1699.2003 ◽

2003 ◽

Vol 47 (5) ◽

pp. 1694-1699 ◽

Cited By ~ 9

Author(s):

Mark J. Shelton ◽

Ross G. Hewitt ◽

John Adams ◽

Andrew Della-Coletta ◽

Steven Cox ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Systemic Exposure ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Minimum Concentration ◽

Mean Values ◽

Immunodeficiency Virus ◽

The Mean ◽

Full Dosage ◽

Delavirdine Mesylate

ABSTRACT To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (± standard deviations) for the maximum concentration in serum (C max) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC0-12), and the minimum concentration in serum (C min) of ritonavir before the addition of delavirdine were 14.8 ± 6.7 μM, 94 ± 36 μM · h, and 3.6 ± 2.1 μM, respectively. These same parameters were increased to 24.6 ± 13.9 μM, 154 ± 83 μM · h, and 6.52 ± 4.85 μM, respectively, after the addition of delavirdine (P is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a C max of 23 ± 16 μM, an AUC0-8 of 114 ± 75 μM · h, and a C min of 9.1 ± 7.5 μM. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.

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Initial Multicenter Experience With Double Nucleoside Therapy for Human Immunodeficiency Virus Infection During Pregnancy

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744998000490 ◽

1998 ◽

Vol 6 (6) ◽

pp. 237-243 ◽

Cited By ~ 8

Author(s):

N. S. Silverman ◽

D. H. Watts ◽

J. Hitti ◽

D. M. Money ◽

E. Livingston ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Side Effects ◽

Liver Function ◽

Hiv Infection ◽

Pregnant Women ◽

Nucleoside Analogs ◽

The United States ◽

Outcome Data ◽

Nucleoside Analog ◽

Immunodeficiency Virus

Objective:To study maternal and neonatal effects of combination nucleoside analog therapy administered to human immunodeficiency virus (HIV)-infected pregnant women for maternal indications.Methods:A multicenter, prospective observational study was undertaken at six perinatal centers in the United States and Canada that supported regional referral programs for the treatment of HIV-infected pregnant women. Demographic, laboratory, and pregnancy outcome data were collected for 39 women whose antiretroviral treatment regimens were expanded to include more than one nucleoside analog for maternal indications. The 40 newborns were monitored at pediatric referral centers through at least three months of age to ascertain their HIV infection status.Results:For all 39 women, zidovudine (ZDV) therapy was instituted at 13.4 ± 8.2 weeks, with a second agent (lamivudine [3TC] in 85% of cases) being added at a mean gestational age of 17.6 weeks. Duration of therapy with two agents was 20.6±10.4 weeks overall, with no women stopping medications because of side effects or toxicity. No significant changes in maternal laboratory values were seen, except for an increase in mean corpuscular volume, over the course of pregnancy. No clinically significant adverse neonatal outcomes were noted, with all but the three preterm newborns leaving hospital with their mothers. Neonatal anemia (hematocrit < 50%) was seen in 62% of newborns, with no children needing transfusion; mild elevations of liver function tests, primarily aspartate aminotransferase, were noted in 58% of newborns tested, though none were clinically jaundiced. Overall rate of neonatal HIV infection was 2.5% (95% confidence interval: 0.1–13.2%).Conclusion:Combination antiretroviral therapy during pregnancy with two nucleoside analogs was well-tolerated by mothers and newborns, with no significant short-term toxicities or side effects noted. Surveillance of exposed newborns’ hematologic and liver function appears warranted.

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Changes in Biochemical Parameters in Human immunodeficiency virus Infected Patients: A Pre-Treatment Study

Journal of BioMedical Research and Clinical Practice ◽

10.46912/jbrcp.42 ◽

2018 ◽

Vol 1 (1) ◽

pp. 95-101

Author(s):

D O Ochalefu ◽

H A Abu ◽

E OO Amali ◽

A S Agada ◽

I E Alonyenu

Keyword(s):

Human Immunodeficiency Virus ◽

Alkaline Phosphatase ◽

Biochemical Parameters ◽

Density Lipoprotein ◽

The Body ◽

Mean Values ◽

Immunodeficiency Virus ◽

The Mean ◽

Pre Treatment ◽

Conjugated Bilirubin

In recent times there have been advances in the management of Human Immunodeficiency Virus infection. However, the disease still poses threat to biochemical parameters of the body. This study was carried out to investigate the biochemical parameters in Human Immunodeficiency Virus infected patients who were yet to start anti-Retroviral drugs regimen. This study was carried out for a period of six weeks using structural questionnaires. A total of one hundred participants were used for the study out of which fifty were Human Immunodeficiency Virus infected while the remaining fifty were Human Immunodeficiency Virus negative, who served as control. There were significant differences (p<0.05) in the values of Total Protein, Albumin, Alkaline Phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Total Cholesterol, High Density Lipoprotein Cholesterol, Triacylglycerol, Calcium and Sodium of Human Immunodeficiency Virus positive patients when compared with the control. However, there were no significant differences (p>0.05) between the mean values of the conjugated Bilirubin, Urea, Creatinine, Potassium, Bicarbonate and Chloride of the infected patients when compared with those of the control. The findings in this study showed significant changes in biochemical parameters in Human Immunodeficiency Virus infected subjects.

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Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in Human Immunodeficiency Virus Type 1-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.609 ◽

1999 ◽

Vol 43 (3) ◽

pp. 609-615 ◽

Cited By ~ 40

Author(s):

Walter Hughes ◽

James A. McDowell ◽

Jerry Shenep ◽

Patricia Flynn ◽

Mark W. Kline ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Body Weight ◽

High Performance ◽

Age Groups ◽

Area Under The Curve ◽

Oral Solution ◽

Parameter Estimates ◽

Immunodeficiency Virus ◽

The Mean

ABSTRACT Abacavir (formerly 1592U89) is a potent 2′-deoxyguanosine analog reverse transcriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase I study was conducted to evaluate the pharmacokinetics and safety of abacavir following the administration of two single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected children ages 3 months to 13 years. Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was rapidly absorbed, with the time to the peak concentration in plasma occurring within 1.5 h postdosing. Pharmacokinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (C max) and the mean area under the curve from time zero to infinity (AUC0–∞) increased by 16 and 45% more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (C max increased from 1.69 to 3.94 μg/ml, and AUC0–∞ increased from 2.82 to 8.09 μg · h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. The mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the dose increased. Neither body surface area nor creatinine clearance were correlated with pharmacokinetic estimates at either dose. The extent of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight. In conclusion, this study showed that abacavir is safe and well tolerated in children when it is administered as a single oral dose of 4 or 8 mg/kg.

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Heparin Cofactor II Deficiency in Patients Infected with the Human Immunodeficiency Virus

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649660 ◽

1993 ◽

Vol 70 (05) ◽

pp. 730-735 ◽

Cited By ~ 27

Author(s):

P Toulon ◽

M Lamine ◽

I Ledjev ◽

T Guez ◽

M E Holleman ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Absolute Number ◽

Thrombin Inhibitor ◽

Unusual Complication ◽

Healthy Individuals ◽

Heparin Cofactor Ii ◽

Immunodeficiency Virus ◽

Coagulation Inhibitor ◽

The Mean ◽

Cd4 Lymphocytes

SummaryIn human plasma, heparin cofactor II (HCII) is a thrombin inhibitor, whose deficiency has been reported to be associated with recurrent thrombosis. The finding of two cases of low plasma HCII activity in two patients infected with the human immunodeficiency virus (HIV) led us to investigate this coagulation inhibitor in the plasma of a larger population of HIV-infected patients. The mean plasma HCII activity was significantly lower in 96 HIV-infected patients than in 96 age- and sex-matched healthy individuals (0.75 ± 0.24 vs 0.99 ± 0.17 U/ml, p <0.0001). HCII antigen concentration was decreased to the same extent as the activity. The proportion of subjects with HCII deficiency was significantly higher in the HIV-infected group than in healthy individuals (38.5% vs 2.1%). In addition, HCII was significantly lower in AIDS patients than in other HIV-infected patients, classified according to the Centers for Disease Control (CDC) on the basis of an absolute number of circulating CD4+ lymphocytes below 200 x 106/1. The link between HCII and immunodeficiency is further suggested by significant correlations between HCII activity and both the absolute number of CD4+ lymphocytes and the CD4+ to CD8+ lymphocyte ratio. Nevertheless, the mean HCII level was not different in the various groups of patients classified according to clinical criteria, except in CDC IVD patients in whom HCII levels were significantly lower. In addition, no correlation could be demonstrated between HCII and protein S activities, another coagulation inhibitor whose plasma level was also found to be decreased in HIV-infected patients. A similar prevalence of HCII deficiency was also found in a small series of 7 HIV-infected patients who developed thrombotic episodes, an unusual complication of the infection. This suggests that, in HIV-infected patients, HCII deficiency is not in itself the causative factor for the development of thrombosis.

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PERIODONTAL DISEASE STATUS, KNOWLEDGE, ATTITUDE, PRACTICE AND TREATMENT NEEDS OF PREGNANT WOMEN

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2018.6.18 ◽

2018 ◽

Vol 8 (6) ◽

pp. 138-144

Author(s):

Thien Nguyen Duc ◽

Tai Tran Tan

Keyword(s):

Periodontal Disease ◽

Pregnant Women ◽

Oral Hygiene ◽

Disease Status ◽

Incidence Rates ◽

Gestation Period ◽

Treatment Needs ◽

Cross Sectional ◽

Mean Values ◽

The Mean

Background: Periodontal disease is a prominent and important issue of public health, especially in pregnant women. The objective of this study is to describe the clinical characteristics; learn knowledge, attitudes, practice oral hygiene and assess the need for treatment of periodontal disease in pregnant women. Subjects and Methods: A cross-sectional study of 210 pregnant women who visited the Department of Obstetrics and Gynecology at the Hue University of Medicine and Pharmacy Hospital. Clinical examination and interview questions on knowledge, attitudes and practice of oral care for all subjects. Results: The incidence of gingivitis was 100%, with mild gingivitis of 4,3% and moderate gingivitis of 95.7%. There was a difference in incidence rates of gingivitis in the gestational period (p<0.001). The incidence of periodontitis is 17.6% and there is no difference in gestational age (p>0.05). The mean values of GI and BOP indices differed by gestation period (p<0.05) and PD, OHI-S, PlI have statistically significant relationship with gestation period (p>0.05). The incidence of periodontal disease is 80.5%; The percentage of pregnant women who abstain from brushing their teeth after birth is 61.4%. Prevalence of brushing once a day: 7.1%; Twice a day: 70.5% and 3 times daily: 22.4%; The mean values of GI, PD, BOP, OHI-S and PlI were inversely proportional to the number of brushing (p<0.001). The rate of dental hygiene is just 3.3%; The rate of oral hygiene, dental plaque and plaque removal was 94,3%; The proportion of subjects required for intensive treatment is 2.4%. Conclusion: Periodontal disease, especially for pregnant women, is high. It is necessary to educate the knowledge, attitudes and practice of proper oral hygiene and to better meet the demand for periodontal disease treatment for pregnant women. Key words: Periodontal disease, pregnant women, knowledge, attitude, practice for oral hygiene, treatment needs

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Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(β-d-Dioxolane)Thymine Triphosphate

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00119-07 ◽

2007 ◽

Vol 51 (6) ◽

pp. 2078-2084 ◽

Cited By ~ 11

Author(s):

Johan Lennerstrand ◽

Chung K. Chu ◽

Raymond F. Schinazi

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Nucleoside Analogs ◽

Nucleotide Analogs ◽

Immunodeficiency Virus ◽

Large Panel ◽

Tenofovir Diphosphate

ABSTRACT A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(β-d-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3′-azido-3′-deoxythymidine-5′-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(β-d-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.

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