Helicase-primase as a target of new therapies for herpes simplex virus infections.

The seminal discovery of acyclovir 40 years ago heralded the modern era of truly selective antiviral therapies and this drug remains the therapy of choice for herpes simplex virus infections. Yet by modern standards, its antiviral activity is modest and new drugs against novel molecular targets such as the helicase-primase have the potential to improve clinical outcome, particularly in high-risk patients. A brief synopsis of current therapies for these infections and clinical need is provided to help provide an initial perspective. The function of the helicase-primase complex is then summarized and the development of new inhibitors of the helicase-primase complex, such as pritelivir and amenamevir, is discussed. We review their mechanism of action, propensity for drug resistance, and pharmacokinetic characteristics and discuss their potential to advance current therapeutic options. Strategies that include combinations of these inhibitors with acyclovir are also considered, as they will likely maximize clinical efficacy.

The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.

Infants are at increased risk for morbidity and mortality due to influenza. Until recently, few data were available with which to optimize oseltamivir dosing in this high-risk population. Here, data for 133 infants were pooled from two prospective pharmacokinetic/pharmacodynamic safety studies to develop a population pharmacokinetic model. A three-compartment model with allometric scaling of all clearance and volume parameters described the disposition of oseltamivir and its carboxylate metabolite (OC). Weight dependence, OC clearance, and volume of distribution increased linearly with age. Analyses showed no association between OC exposure and viral clearance, the development of resistance (phenotypic/genotypic), normalization of body temperature, or safety endpoints. Pharmacokinetic bridging showed that a 3 mg/kg dose yielded acceptable OC exposure and good tolerability while minimizing the risk of underexposure and resistance/treatment failure. These pharmacological analyses formed the basis of the US Food and Drug Administration's recent approval of oseltamivir treatment for infants with influenza aged as young as 2 weeks.

Determination of appropriate dosing of influenza drugs in pediatric patients.

Dose-finding studies of influenza antiviral drugs are challenging because it is difficult to enroll subjects in pediatric interventional studies and also because of the lack of concentration (or toxicity)­response relationships, the short duration of antiviral therapy, and the continually developing metabolic profiles of infants and young children. The evaluation of influenza antiviral agents in premature infants adds even more complexity. Recent advances in exposure-targeted study designs and modeling and simulations have aided in addressing some of these challenges.

Cloning and characterization of recombinant rhesus macaque IL-10/Fc(ala-ala) fusion protein: a potential adjunct for tolerance induction strategies.

The powerful anti-inflammatory and immunosuppressive activities of IL-10 make it attractive for supplemental therapy in translational tolerance induction protocols. This is bolstered by reports of IL-10-mediated inhibition of innate immunity, association of human stem cell and nonhuman primate (NHP) islet allograft tolerance with elevated serum IL-10, and evidence that systemic IL-10 therapy enhanced pig islets survival in mice. IL-10 has not been examined as adjunctive immunosuppression in NHP. To enable such studies, we cloned and expressed rhesus macaque (RM) IL-10 fused to a mutated hinge region of human IgG1 Fc to generate IL-10/Fc(ala-ala). RM IL-10/Fc(ala-ala) was purified to approximately 98% homogeneity by affinity chromatography and shown to be endotoxin-free (<0.008 EU/microg protein). The biological activity of IL-10/Fc(ala-ala) was demonstrated by (1) costimulation of the mouse mast cell line, MC/9 proliferation in a dose-dependent fashion, (2) suppression of LPS-induced septic shock in mice and (3) abrogation of LPS-induced secretion of proinflammatory cytokines/chemokines in vitro and in vivo in NHP. Notably, RM IL-10/Fc(ala-ala) had significantly greater potency than human IL-10/Fc(ala-ala) and exhibited a circulating half-life of approximately 14 days. The availability of this reagent will facilitate definitive studies to determine whether supplemental therapy with RM IL-10/Fc(ala-ala) can influence tolerance outcomes in NHP.

Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Pharmacokinetic enhancement of protease inhibitors.

Protease inhibitor (PI)-enhanced regimens are becoming a standard of care in therapy for HIV infection. Many important questions remain regarding the optimal use of this treatment strategy. Multiple physiologic and pathologic factors influence the pharmacokinetic and pharmacodynamic profiles of PIs. Specifically, alterations in drug metabolism associated with inhibition or stimulation of the 3A4 isozyme of the cytochrome P-450 enzyme system, activity of the P-glycoprotein intracellular transport system, and degree of plasma protein binding are all recognized as having important roles in influencing overall plasma PI concentrations and, ultimately, efficacy. Available pharmacokinetic data should include interpatient variation in plasma PI concentrations in addition to mean or median results. Viral inhibitory concentrations that have been corrected for the effect of protein binding should also be standardized. Studies to establish the concentration-response relationship for PIs may also prove beneficial in determining optimal plasma PI concentrations. Currently, therapeutic drug monitoring is not routinely recommended because of a lack of convincing clinical data as well as of a standard approach to collection and interpretation of drug concentrations. Large prospective studies are needed to further advance the usefulness of therapeutic drug monitoring.

Pharmacokinetics of saquinavir-SGC in HIV-infected pregnant women.

PURPOSE: To evaluate saquinavir (SQV) pharmacokinetics, tolerance, and safety in 10 HIV-infected pregnant women between 14-32 weeks gestation. METHOD: This was a phase I, prospective, area-under-the-curve (AUC) targeted study. Antepartum treatment consisted of SQV 1200 mg tid, lamivudine 150 mg bid, and zidovudine 200 mg tid. The SQV targeted exposure was an 8-hour AUC (AUC(8)) of 3000 ng. h/mL; the study was to be halted if the first 4 participants did not achieve this AUC(8). Cord blood and plasma samples were collected in neonates at birth. RESULTS: Four women completed the SQV pharmacokinetic assessments. Exposure in all 4 patients was below the target AUC(8). Median (range) AUC(8) and trough (C8H) were 1672 (738-2614) ng. h/mL and 60 (<15-332) ng/mL, respectively. Oral clearance (CL/F) was 9.3 (5.1-16.6) L/h/kg and C(max) was 599 (177-953) ng/mL. Cord and neonate plasma concentrations were mostly undetectable; 1 of 5 infants was HIV-infected at 24 weeks. CONCLUSION: These data suggest highly variable SQV pharmacokinetics in pregnant women, and exposure at 1200 mg tid may not be adequate for longer term therapy; both the AUC(8) and C8H were considerably below average. Because ritonavir has been shown to significantly increase SQV concentrations, this combination should be further explored in this population.

Combination therapy with indinavir, ritonavir, and delavirdine and nucleoside reverse transcriptase inhibitors in patients with HIV/AIDS who have failed multiple antiretroviral combinations.

PURPOSE: Ritonavir (RTV) and delavirdine (DLV) are inhibitors of cytochrome P450 (CYP) 3A4, the specific CYP that metabolizes indinavir (IDV). We hypothesized that patients who have failed multiple therapies containing protease inhibitors would still respond to IDV if high plasma concentrations were achieved. We retrospectively examined the antiviral efficacy of the combination of RTV, DLV, and IDV in heavily antiretroviral-experienced patients. METHOD: A chart review of patients treated with IDV/RTV/DLV and two nucleoside reverse transcriptase inhibitor (NRTI) drugs was performed. Only patients who failed at least three highly active antiretroviral therapy (HAART) regimens and remained on IDV/RTV/DLV therapy for at least 2 months were included. Plasma concentrations for IDV and RTV were obtained if patients were still on therapy. RESULTS: Ten participants were identified who qualified for this study. The median plasma HIV RNA prior to initiating IDV/RTV/DLV was 359,300 copies/mL. Nine of the 10 patients had failed nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens in the past. Eight out of 10 patients had at reduction in HIV RNA. Four of eight patients maintained the 1 log(10) reduction in HIV RNA past 6 months. Mean CD4 cell count increased from 142+/-99 to 273+/-126 cells/mm(3). Genotypic data available on six patients showed multiple protease gene mutations. Plasma concentration of IDV in three patients (two troughs and one 7 hours postdose) were >1,000 ng/mL. CONCLUSION: Our data suggests that in heavily antiretroviral drug-treated patients, partial antiretroviral response to RTV/IDV/DLV can still be achieved. The use of IDV/RTV/DLV and two NRTIs as salvage therapy has merit in patients who have no viable treatment options. A prospective trial utilizing this drug combination is warranted.

Acyclovir for treatment of postherpetic neuralgia: efficacy and pharmacokinetics.

Postherpetic neuralgia is the most common complication of herpes zoster (shingles) in the immunocompetent host. Its mechanism is incompletely understood, but one postulate is that continuous replication of varicella-zoster virus (VZV) in nerve tissues may be responsible for the pain. If this is so, antiviral treatment could be advantageous. To test this hypothesis, we performed a randomized, double-blind, placebo-controlled trial of intravenous acyclovir (10 mg/kg every 8 h [q8h]) for 14 days, followed by oral acyclovir (800 mg q6h) for 42 days in 10 subjects (median age, 71 years) who had experienced at least 6 months of severe pain (median duration of postherpetic neuralgia before enrollment, 3.2 years). Intensive and sparse pharmacokinetic sampling occurred during both dosing phases of the study. One- and two-compartment models were fitted to the oral and intravenous concentration-time data, respectively. The four men and four women assigned to acyclovir during either or both dosing phases tolerated it well. Pharmacokinetic results were similar to those previously reported in younger individuals. The mean oral clearance and elimination half-life following oral dosing were 1.47 liters/h/kg and 2.78 h, respectively. Total clearance and terminal half-life following intravenous administration were 0.16 liters/h/kg and 3.67 h, respectively. Only 1 of 10 participants reported definite improvement in the severity of postherpetic pain, and treatment had no effect on titers of humoral antibody to VZV. We concluded that 56 days of intravenous and oral acyclovir therapy were well tolerated but had little or no effect on the clinical course of postherpetic neuralgia.

Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir.

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

Phase I dose escalation pharmacokinetics of O-(chloroacetylcarbamoyl) fumagillol (TNP-470) and its metabolites in AIDS patients with Kaposi's sarcoma.

The pharmacokinetics of TNP-470 and its major metabolites were investigated in AIDS patients enrolled in a phase I dose escalation trial for the treatment of Kaposi's sarcoma. The patients received TNP-470 by 1-h intravenous infusion in dose cohorts of 10, 20, 30, 40, 50 and 70 mg/m2. The parent drug and metabolites, MII and MIV, were measured by high-performance liquid chromatography/mass spectrometry (HPLC/MS) in plasma samples collected during and out to 168 h after the beginning of the infusion. Both metabolites were detected in all patients' plasma, while the parent drug was undetectable at time-points as early as 5 min after the end of infusion for some patients. A large interpatient variability of pharmacokinetic parameters among the dosing cohorts was observed for TNP-470, with a mean (+/- SD) plasma elimination half-life (t1/2) of 0.06 +/- 0.04 h, plasma clearance (CL) of 1487 +/- 1216 l/h and an area under the concentration versus time curve (AUC) of 49.9 +/- 35.8 ng/ml x h. Time to maximum plasma concentration (Tmax) typically occurred before the end of the infusion. The predominant plasma metabolite was MII with a t1/2 of 1.21 +/- 0.43 h, AUC of 1226 +/- 2303 l/h and a Tmax occurring between 5 and 15 min after infusion. The reported active metabolite MIV had a t1/2 of 0.24 +/- 0.13 h, AUC of 24.9 +/- 32.6 ng/ml x h and a Tmax occurring between the midpoint of the infusion and 15 min after infusion. The parent drug was undetectable by HPLC/MS/MS in urine samples collected and pooled between 0-6 and 6-24 h from the beginning of drug administration. Metabolite MIV was present in the 0-6-h urine pool of two patients enrolled in the highest dosing cohorts, equivalent to 0.4% of the administered dose. Metabolite MII was present in all 0-6-h samples analyzed and represented 1.12 +/- 0.9% of the administered dose. Renal clearance (CLR) for MII was 140 +/- 70 ml/h.

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Pharmacodynamics of human immunodeficiency virus type 1 protease inhibitors.

Many factors are involved in the success or failure of antiretroviral therapy. Recent data suggest that there are significant differences in drug absorption and disposition for the protease inhibitor class of antiretroviral drugs, and relationships between plasma concentrations and their antiviral effect have been described. Consequently, the issue of whether therapeutic drug monitoring should be employed for patients receiving treatment with these drugs has arisen. Several criteria must be met before a drug is considered a candidate for therapeutic drug monitoring. These criteria include pharmacological, clinical, and analytic components. Although not all the necessary criteria have yet been met, some of these components have been defined, and additional data are being generated. However, prospectively designed clinical trials must be completed to determine if monitoring protease inhibitor plasma concentrations provides additional clinical benefit to the patient.

Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884.

OBJECTIVE: To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DESIGN: Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SETTING: Multicenter study of the AIDS Clinical Trials Group (ACTG). PATIENTS: HIV-infected subjects. INTERVENTIONS: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. MAIN OUTCOME MEASURES: Area under the concentration-time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. RESULTS: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. CONCLUSIONS: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.

Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients.

OBJECTIVES: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. METHODS: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. RESULTS: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. CONCLUSIONS: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.

Indinavir concentrations and antiviral effect.

STUDY OBJECTIVES: To determine the variability of indinavir pharmacokinetics in patients attending an outpatient clinic, and to explore relationships between indinavir exposure and antiviral effect. DESIGN: Open, formal pharmacokinetic evaluation. SETTING: University-affiliated clinical research center. PATIENTS: Forty-three adults infected with the human immunodeficiency virus (HIV) receiving therapy with indinavir and concomitant nucleoside reverse transcriptase inhibitors. INTERVENTION: Indinavir concentrations were measured after patients were observed taking an 800-mg oral dose, and pharmacokinetic parameters were determined using a one-compartment oral absorption model. Virologic and pharmacologic characteristics were compared in a subset of 23 patients who were protease inhibitor naive before receiving indinavir. MEASUREMENTS AND MAIN RESULTS: Mean indinavir pharmacokinetics were similar to those reported previously. Significant intersubject variability in systemic exposure was observed in patients receiving the same dosage; the 8-hour area under the curve (AUC8) ranged from 5.4-68.0 microM x hour. In protease inhibitor-naive subjects, the indinavir AUC8 was statistically higher in those with undetectable plasma HIV RNA (30.7 microM x hr) versus detectable plasma HIV RNA (22.4 microM x hr, p=0.035). Measured concentrations 5 hours after the dose and extrapolated 8-hour concentrations were also significantly higher in patients with undetectable plasma HIV RNA (both p=0.007). CONCLUSIONS: Indinavir plasma concentrations were highly variable among patients receiving the same dosage. Patients with an undetectable plasma HIV RNA level who were protease inhibitor naive had statistically higher indinavir concentrations and slower oral clearance than the group with detectable HIV RNA. Relationships between indinavir concentrations and anti-HIV effect provide a basis for quantifying the pharmacologic contribution to the heterogeneity in therapeutic response.

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.

Pharmacokinetics and safety of concentration-controlled oral zidovudine therapy.

STUDY OBJECTIVE: To evaluate the pharmacokinetics, safety, and feasibility of concentration-controlled oral zidovudine therapy. DESIGN: Randomized, crossover, open-label study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight individuals infected with the human immunodeficiency virus with CD4+ lymphocyte counts of 100 cells/microliter or greater. INTERVENTION: During the 24-week study, patients received oral zidovudine regimens that consisted of a standard fixed dose of 500 mg/day and a concentration-controlled regimen designed to maintain a steady-state plasma concentration (Css) of 0.187 +/- 0.04 mg/L (0.7 +/- 0.14 microM). MEASUREMENTS AND MAIN RESULTS: The mean Css during standard therapy was 0.170 +/- 0.024 mg/L versus 0.205 +/- 0.021 mg/L with the concentration-controlled regimen (p = 0.025). Respective mean changes in hemoglobin were -0.02 g/dl (range -0.9-0.9 g/dl) and -0.30 g/dl (range -1.5-0.4 g/dl, p = 0.67). The absolute neutrophil count decreased 0.90 x 10(9)/L during standard therapy and increased 0.40 x 10(9)/L during concentration-controlled therapy (p = 0.07). The regimens did not differ in toxicity. CONCLUSION: Concentration-controlled oral antiretroviral therapy with zidovudine is feasible and safe, and provides pharmacologic data to determine the regimen's virologic and immunologic benefits.