Potential confusion with antiretroviral drugs.
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Anti-HIV Agents↗
Biomedical subjects
C V Fletcher
Publications and source records attributed to C V Fletcher.
Concentration-controlled zidovudine therapy.
BACKGROUND: Heterogeneity in the response to antiretroviral therapy has been attributed to pharmacologic, immunologic, and virologic differences between patients. Currently available antiretroviral agents used for the treatment of human immunodeficiency virus (HIV) infection in adults are administered in standard fixed doses. The active moiety of nucleoside anti-HIV drugs is the intracellular anabolite. Therefore the heterogeneity in response to nucleoside agents may arise as a result of pharmacologic variability at both the systemic and cellular level. OBJECTIVES: To determine whether a novel concentration-controlled zidovudine regimen could improve anti-HIV response compared with the standard fixed-dose approach. DESIGN: At the Outpatient Clinic of the General Clinical Research Center at the University of Minnesota, 20 persons with HIV infection received an oral regimen of zidovudine designed to achieve a target concentration in plasma of 0.7 mumol/L and the 500 mg/day standard dose in a randomized, crossover 24-week study. RESULTS: The concentration-controlled regimen achieved overall higher systemic concentrations with reduced interpatient variability: steady-state average zidovudine plasma concentrations were 0.76 mumol/L (coefficient of variation, 12%) versus 0.62 mumol/L (coefficient of variation, 32%) for the standard regimen. There was no difference in safety and tolerance between regimens. Intracellular zidovudine triphosphate concentrations averaged 160 fmol/10(6) peripheral blood mononuclear cells (PBMCs) with concentration-controlled versus 92 fmol/10(6) PBMCs for standard therapy. The percentage change from baseline in CD4 cells was a 22% increase for the concentration-controlled regimen versus a 7% decrease with standard therapy. CONCLUSIONS: These data indicate that pharmacologic variability affects antiretroviral response. Furthermore, these findings provide a framework to characterize the pharmacologic determinants of effect and quantitate their contribution to the heterogeneity in clinical response to optimize therapeutic benefit.
Adult↗
A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddI) in children infected with the human immunodeficiency virus.
Twelve children infected with the human immunodeficiency virus were treated orally with indinavir, stavudine, plus didanosine for 12 to 48 weeks. Therapy was limited in some cases by nonadherence, intolerance, toxicity, and virologic failure. Marked increases in CD4+ lymphocyte counts and decreases in plasma human immunodeficiency virus RNA concentrations suggest that the regimen has potent antiviral activity.
Administration, Oral↗
Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group.
The pharmacokinetics and safety of hyperimmune anti-human immunodeficiency virus (HIV) intravenous immunoglobulin (HIVIG) were evaluated in the first 28 maternal-infant pairs enrolled in a randomized, intravenous immunoglobulin (IVIG)-controlled trial of HIVIG maternal-infant HIV transmission prophylaxis. Using 200 mg/kg, mean half-life and volume of distribution (Vd) in women were 15 days and 72 mL/kg, respectively, after one and 32 days and 154 mL/kg after three monthly infusions, with stable 4 mL/kg/day clearance. Transplacental passage occurred. Newborn single-dose half-life, Vd, and clearance were 30 days, 143 mL/kg, and 4 mL/kg/day, respectively. HIVIG rapidly cleared maternal serum immune complex-dissociated p24 antigen, and plasma HIV-1 RNA levels were stable. Mild to moderate adverse clinical effects occurred in 2 of 103 maternal and 2 of 25 infant infusions. No adverse hematologic, blood chemistry, or immunologic effects were seen. HIVIG is well-tolerated in HIV-infected pregnant women and their newborns, clears antigenemia, crosses the placenta, and exhibits pharmacokinetics similar to those of other immunoglobulin preparations.
Adolescent↗
Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS.
Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.
Acquired Immunodeficiency Syndrome↗
Valacyclovir.
OBJECTIVE: To discuss the clinical pharmacology, antiviral activity, clinical efficacy, and other therapeutic issues associated with valacyclovir use for the treatment of herpesvirus infections. DATA SOURCE: Literature searches using MEDLINE were prospectively designed to include relevant articles and abstracts between January 1982 and March 1996. The searches focused on valacyclovir pharmacology, clinical efficacy, and issues associated with herpesvirus infections. STUDY SELECTION: Selection of clinical and basic science studies were limited to those focusing on valacyclovir. All articles with pertinent information relevant to the scope of this article were reviewed. DATA SYNTHESIS: Valacyclovir is an amino acid ester prodrug of acyclovir. It is currently approved for the treatment of herpes zoster infections in immunocompetent adults (1 g p.o. tid for 7 d) and recurrent episodes of genital herpes in immunocompetent adults (500 mg bid for 5 d). Valacyclovir is rapidly and almost completely hydrolyzed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir. At higher dosages (2 g qid), the plasma AUC of acyclovir following oral valacyclovir administration approximates that seen after intravenous administration of 10 mg/kg every 8 hours. Clinical data indicate that valacyclovir is at least as effective as acyclovir in decreasing the duration of pain associated with postherpetic neuralgia, and in reducing time to genital lesion healing and the length of the episode. CONCLUSIONS: Valacyclovir has improved bioavailability over acyclovir and is at least as efficacious. The favorable safety profile of acyclovir and increased systemic exposure make it a particularly ideal candidate for further studies of herpes group viral infections in immunocompromised patients.
Acyclovir↗
Disposition of zidovudine in obese pregnant women with human immunodeficiency virus type 1 infection.
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Female↗
Effect of foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with AIDS.
Four intravenous dosages of foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak foscarnet concentration (P < 0.01) and the area under the foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.
AIDS-Related Opportunistic Infections↗
Pharmacologic considerations for antiviral drug development.
OBJECTIVE: To discuss pharmacologic considerations for the development of antiviral agents. DATA SOURCES: English-language literature pertaining to the development and clinical evaluation of antiviral compounds, primarily agents targeted against herpes group viruses and HIV. STUDY SELECTION AND DATA EXTRACTION: Pertinent information, as judged by the author, was selected for discussion. DATA SYNTHESIS: Drug development of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critical to developing a rational dosing strategy and safe, effective use. The lack of standardized methods for antiviral susceptibility testing and the influence of factors such as strain of virus, host cell type, culture medium, inoculum size, end point, and method of measurement on the results obtained illustrate factors that complicate preclinical pharmacologic analysis of antiviral agents. Acyclovir offers a model for clinical drug development. Its mechanism of action, pharmacokinetics, and pharmacodynamics have been studied extensively. Rational guidelines for usage are available, including guidelines in special patient populations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral drug development are associated with inadequate pharmacologic information. The development of dextran sulfate and fialuridine provides two examples. Integration of pharmacokinetic and pharmacodynamic analyses using modern sampling and analysis techniques may facilitate more rapid development of antiviral agents and more informed dosage regimens to achieve the highest probability of therapeutic success.
Antiviral Agents↗
Clinical pharmacokinetics of zidovudine. An update.
The battle against the acquired immune deficiency syndrome (AIDS) is now into its second decade, and substantial advancements have been made in our understanding of the complex life cycle of, and the immunopathology associated with, human immunodeficiency virus (HIV) infection, as well as of the drugs used to modify the course of disease. Zidovudine was the first agent approved for treatment of HIV disease, and since its widespread availability in 1987 the pharmacokinetic disposition and clinical effects of zidovudine have been extensively evaluated. This article reviews the absorption, distribution, metabolism and elimination characteristics of zidovudine, focusing on more recent information. In addition, factors that may or may not affect zidovudine disposition are discussed. These include selected drug interactions and concomitant disease states such as renal and hepatic insufficiency. Issues such as bodyweight normalisation, maternal-fetal transfer, pregnancy and intracellular phosphorylation are discussed in relation to the pharmacokinetics and clinical efficacy of zidovudine. Finally, information regarding the clinical pharmacodynamics of zidovudine is presented. This includes possible relationships between zidovudine pharmacokinetics and markers of efficacy and toxicity, and the significance of linking pharmacokinetic and pharmacodynamic information.
Age Factors↗
Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects.
OBJECTIVES: To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection. METHODS: Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42 cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. RESULTS: Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4 + lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively. CONCLUSIONS: Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease.
Antiviral Agents↗
Pentamidine concentrations in a mother with AIDS and in her neonate.
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AIDS-Related Opportunistic Infections↗
Strategies for control of zidovudine concentrations in serum.
There are several clinical scenarios in which knowledge of zidovudine disposition may be important. This study evaluated the clinical utility of pharmacokinetic parameters for zidovudine derived from sparse serum concentration data obtained in an outpatient setting. Twelve human immunodeficiency virus-infected participants had two serum zidovudine concentrations determinations obtained on two different clinic visits, 2 to 38 days apart. Zidovudine concentrations were measured by radioimmunoassay. A one-compartment oral absorption model was used to describe zidovudine disposition. Three different approaches were used to estimate pharmacokinetic parameters: Bayesian estimation with one or two concentrations and least squares with one concentration. The ability of these parameters to predict concentrations measured during the second clinic visit was assessed by calculation of precision and bias and compared with predictions using standard fixed or weight-adjusted parameters. Estimated pharmacokinetic parameters for zidovudine were consistent with literature values; there was no statistically significant difference among the parameters calculated with the three estimation strategies. Absorptive phase concentrations were poorly predicted by all methods (mean percent bias, 157 to 249%; mean percent precision, 389 to 537%). Predictive ability for concentrations obtained in the elimination phase was strikingly improved: mean percent bias, -17 to 70%; mean percent precision, 40 to 95%. Bayesian and least-squares estimated parameters were statistically better than fixed-parameter values for predicting concentrations in the elimination phase. These observations provide a modeling framework to determine pharmacokinetic disposition of zidovudine in an individual, screen for the existence of a drug interaction, and conduct concentration-controlled clinical trials.
Adolescent↗
Recent advances: antiinfectives.
OBJECTIVE: To update readers on the significant changes in infectious diseases pharmacotherapy. DATA SOURCES: An Index Medicus and Iowa Drug Information Service search (1993-1994) of English-language literature pertaining to the selected topic areas was performed. Additional information from abstracts presented at scientific meetings were identified by the authors. STUDY SELECTION AND DATA EXTRACTION: All identified studies were screened and those judged relevant to the update were evaluated. DATA SYNTHESIS: New or clinically significant data since 1992 that related to peptic ulcer disease, microbial resistance (e.g., Enterococcus spp., Streptococcus pneumoniae, Mycobacterium tuberculosis, Candida albicans), immunomodulators, and AIDS were evaluated and compared with previous data. CONCLUSIONS: There have been several exciting and significant changes in infectious diseases pharmacotherapy evident from this review.
Acquired Immunodeficiency Syndrome↗
Agents for treating human immunodeficiency virus infection.
The replicative cycle of the human immunodeficiency virus (HIV) is reviewed, and currently used and investigational agents directed against the virus are discussed. The first step in the replication of HIV is selective binding of the envelope glycoprotein to CD4 receptors located on T lymphocytes. The virion is then uncoated within the cytoplasm, yielding viral genomic RNA. Reverse transcriptase uses the viral RNA as a template to form single-stranded DNA, which is duplicated to form proviral DNA through the activity of ribonuclease H. Host RNA polymerases transcribe the integrated proviral DNA into messenger RNA, and there is subsequent translation to viral proteins. After translation, further modification of precursor polyproteins is necessary to produce functional peptides. The assembled virus then buds from the cell surface and invades other cells. Targets of drug intervention in the replicative cycle include (1) binding and entry, (2) reverse transcriptase, (3) transcription and translation, and (4) viral maturation and budding. Inhibitors of binding and entry include recombinant soluble CD4, immunoadhesins, peptide T, and hypericin. Nucleoside reverse-transcriptase inhibitors include zidovudine, didanosine, zalcitabine, and stavudine. Foscarnet, tetrahydroimidazobenzo-diazepinthione compounds, and nevirapine are some nonnucleoside reverse-transcriptase inhibitors. Inhibitors of transcription and translation include antagonists of the tat gene and GLQ223. Castanospermine, N-butyldeoxynojirimycin, and protease inhibitors interfere with viral maturation and budding. Drug combinations that have been or are being investigated include zidovudine plus interferon alfa, zidovudine plus zalcitabine, and zidovudine plus didanosine. Four agents currently have approved labeling for use against HIV infection: zidovudine, didanosine, zalcitabine, and stavudine. Monotherapy with zidovudine remains the treatment of first choice. Although progress has been made in developing drug therapies for HIV infection, more selective and more potent drugs are urgently needed. The best approach at present is to optimize the use of available agents, continue to investigate new therapies, and educate the public about prevention.
Antiviral Agents↗
Gender differences in human pharmacokinetics and pharmacodynamics.
Gender differences in pharmacokinetics and pharmacodynamics have long been recognized in animals. In humans, however, little attention has been paid to this field despite at least theoretical reasons to believe that gender may be an important variable in the processes of absorption, distribution, metabolism, and excretion. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, amount of drug binding proteins, gender-specific cytochrome P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and renal blood flow are several factors that may contribute to sex-related differences in pharmacokinetics. Clinical investigations have documented greater absorption and subsequent incorporation of iron into erythrocytes, and higher bioavailability of ethanol in females. Women have been shown to have a slower metabolism of mephobarbital and propranolol but an increased biotransformation of methylprednisolone, all three of which are metabolized by enzymes of the cytochrome P450 system. Lastly, the renal excretion of amantadine was inhibited significantly by quinidine and quinine in men but not in women. While gender-specific pharmacodynamic data are meager, evidence also supports the existence of sex-related differences. Women appear to be more prone to develop torsades de points from drugs such as quinidine and procainamide than men. A dimorphism in insulin sensitivity has been demonstrated with males having an enhanced response compared to females. Pharmacokinetic and pharmacodynamic sex-related differences exist and are complex. Future research efforts should be designed to provide more gender-specific information on drug disposition and clinical effect.
Adolescent↗
Foscarnet for suppression of human immunodeficiency virus replication.
The effect of foscarnet against human immunodeficiency virus (HIV) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.
Adult↗
Introduction to the "HIV and AIDS" column.
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Acquired Immunodeficiency Syndrome↗