Determination of abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine concentration in human plasma by MALDI-TOF/TOF.

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 x 10(-2)-1.00 pmol/microL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 x 10(-2)-1.00 pmol/microL. The limit of quantification value was 1.00 x 10(-2)pmol/microL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentration which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 microM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10- to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in approximately 5-fold and approximately 15-fold lower ratios of ddCTP/dCTP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase. We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy.

A new model for the population pharmacokinetics of didanosine in healthy subjects.

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0%, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2%, respectively. The relatively high (>30%) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

Estimating the genetic component (RGC) in pharmacokinetic variability of the antiretroviral didanosine among healthy Brazilians.

BACKGROUND: We estimate the variance between between- and within-subjects, using mixed effect models, as a way to assess the genetic component in explaining the observed heterogeneity of ddl kinetics among healthy individuals. Our work expands on a previous reported method known as RGC. METHODS: Repeated measurements of ddl concentration in the serum were obtained from 48 healthy adult volunteers enrolled in two bioequivalence study. We use the NONMEM program (Non-linear Mixed Effect Model) to estimate the between- and within-subject variability and the corresponding pharmacokinetic parameters. We assess the genetic contribution to the variability of each pharmacokinetic parameter through the RGC method. RESULTS: Pharmacokinetic parameters, expressed as functions of covariates gender and creatinine clearance (CLCR), were: Oral clearance (CL = 55.1 + 240 * CLCR + 16.6 l/h for male and CL = 55.1 + 240 * CLCR for female), central volume (V2 = 9.82), inter-compartmental clearance (Q = 40.90/h), peripheral volume (V3 = 62.7 + 22.90 for male and V3 = 62.70 for female), absorption rate constant (Ka = 1.51 h(-1)) and duration of the dose administration (D = 0.44 h). The RGC of CL, Q, V3, Ka and D were 0.58, 0.97, 0.60, 0.53 and 0.88, respectively. CONCLUSION: We estimated parameter-specific RGC indices and rank them according to the potential genetic contribution as an explanation for the observed variance. Our study design improved precision by decreasing background noise and, thus, improved the chances that indices such as the RGC are in fact describing genetic variability.

Drug-drug and drug-food interactions between tenofovir disoproxil fumarate and didanosine.

The drug-drug and drug-food interactions between tenofovir DF and didanosine EC were evaluated in 2 pharmacokinetic studies in healthy adult subjects. When 400 mg was dosed with tenofovir DF, mean didanosine AUC was increased by 44% to 60% following fasted or fed administration. Staggered coadministration (2 hour, fasted) of a reduced didanosine dose of 250 mg resulted in equivalent didanosine exposure, while simultaneous administration with tenofovir DF in the fasted and fed state resulted in didanosine AUCs similar to that of the reference treatment of 400 mg alone in the fasted state. These data indicate that a dose reduction of didanosine is warranted when it is used with tenofovir DF. The drug-drug-food interaction of didanosine may offer more flexible dosing of didanosine EC when it is used with tenofovir DF. Patients receiving tenofovir DF and didanosine together should be carefully monitored for safety and efficacy.

Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography.

A reversed phase high performance liquid chromatography method was developed for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, didanosine, stavudine, zidovudine and abacavir in plasma. The method involved solid-phase extraction with Oasis MAX cartridges from plasma, followed by high performance liquid chromatography with a SymmetryShield RP 18 column and ultraviolet detection set at a wavelength of 260 nm. The assay was validated over the concentration range of 0.015-5 mg/l for all five NRTIs. The average accuracies for the assay were 92-102%, inter- and intra-day coefficients of variation (CV) were <2.5% and extraction recoveries were higher than 97%. This method proved to be simple, accurate and precise, and is currently in use in our laboratory for the quantitative analysis of NRTIs in plasma.

Simultaneous determination of 2',3'-dideoxyinosine and the active metabolite, 2',3'-dideoxyadenosine-5'-triphosphate in human peripheral-blood mononuclear cell by HPLC-MS/MS and the application to cell pharmacokinetics.

A specific and reliable HPLC-MS/MS method was developed and validated for the simultaneous determination of 2',3'-dideoxyinosine (ddI) and the active metabolites, 2',3'-dideoxyadenosine-5'-triphosphate (ddA-TP) in human peripheral-blood mononuclear cell for the first time. The analytes were separated on a HILIC column (100mm×2.1mm, 1.7µm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization (ESI) source was used for detection. The cell homogenates sample was prepared by the solid phase extraction. The calibration curves were linear over a concentration range of 0.5-200.0ng/mL for ddI and 0.25-100.0ng/mL for ddA-TP. The intra-day and inter-day precision was less than 15% and the relative error (RE) were all within ±15%. The validated method was successfully applied to assess the disposition characteristics of ddI and support cell pharmacokinetics after the patients with AIDS were orally administrated with ddI and tenofovir disoproxyl fumarate (TDF).

Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV-1 infected individuals.

OBJECTIVE: To compare the plasma pharmacokinetics of didanosine during once daily (qd) and twice daily (bid) dosing. DESIGN: Open-label, randomized, cross-over study. METHODS: HIV-1 infected patients who used didanosine were randomized to either a qd or a bid dosing regimen of didanosine. The total daily dose of didanosine was identical in both regimens. Seven days after the start of the study, the pharmacokinetic profile of didanosine in plasma and urine was assessed during an 8-h period. The next day, the patient was switched to the opposite dosing regimen, and after another 7 days, the study was concluded by again assessing the plasma and urine pharmacokinetics of didanosine during 8 h. RESULTS: A total of 19 patients completed the study. The pharmacokinetics of didanosine in plasma (with maximum plasma concentration adjusted for dose) and urine were not significantly different in the qd and bid dosing regimen (P > 0.28 for all parameters). CONCLUSION: We conclude that qd dosing of didanosine leads to a similar exposure in plasma as bid dosing (using the same total daily dose). Since qd dosing may lead to improved compliance of patients to regimens containing didanosine, these results provide a rationale for prescribing didanosine in a qd regimen, and is reassuring when we realize that the drug is being administered in a qd dosing regimen on a large scale in clinical practice.

The Alpha trial: European/Australian randomized double-blind trial of two doses of didanosine in zidovudine-intolerant patients with symptomatic HIV disease. Alpha International Coordinating Committee.

OBJECTIVES: To compare the efficacy and toxicity of two doses of didanosine (ddI) in patients with symptomatic HIV disease who are intolerant of zidovudine (ZDV). DESIGN: The Alpha trial is a randomized double-blind multicentre trial of two doses of ddI. ddI was given as one buffered sachet twice daily in doses adjusted for weight: 750 mg per day for patients > or = 60 kg in the higher-dose group, and 200 per day for the lower-dose group. RESULTS: Patients (n = 1775; 907 higher-dose, 868 lower-dose) from nine European countries and Australia were randomized and started trial treatment. Sixty per cent had AIDS, 65% had CD4 cell counts < 50 x 10(6)/l and 55% had received ZDV for more than 12 months. Follow-up was to death or 30 September 1992, and only 33 patients (20 higher-dose, 13 lower-dose) had been lost to follow-up for at least 3 months at that time. The longest follow-up was 28.5 months and the mean (SD) was 12.4 (6.9) months. There was no significant difference in survival between the groups: 67% of patients in each group died, the median survival being 13.0 months in the higher-dose and 12.5 in the lower-dose groups, a difference of about 0.5 months (95% confidence interval, -0.9 to 2.0; log-rank P = 0.7). There was also no significant difference in progression to AIDS or death, development of HIV encephalopathy or death, or development of new AIDS events or death. There were small (but statistically significant) differences in the changes in CD4 cell count and in p24 antigen levels between the groups, with greater increases in CD4 and greater decreases in p24 in the higher-dose group. There were also clear differences in adverse events: pancreatitis developed more frequently in the higher-dose group, 66 patients compared to nine patients in the lower-dose group, of whom 37 and six, respectively, were classified as definite cases. Nine cases (seven higher-dose, two lower-dose) were reported to have died because of or with pancreatitis. Peripheral neuropathy, abnormal liver function and dry mouth were also reported more often in the higher-dose group. CONCLUSIONS: The Alpha trial is not able to provide direct evidence for the clinical efficacy of ddI. There was no significant difference between the two doses in mortality or disease progression. However, the higher dose was more toxic.

The extent of non-adherence in a large AIDS clinical trial using plasma dideoxynucleoside concentrations as a marker.

OBJECTIVES: To assess adherence to study medications in an AIDS clinical trial, to evaluate whether study participants adhered to only one component of a multidrug regimen ('differential adherence'), and to determine whether there was evidence of non-uniform adherence to study medications among treatment groups. SETTING: This was a substudy of AIDS Clinical Trials Group protocol 175, a large, double-blind, randomized study of monotherapy versus combination dideoxynucleoside therapy. Participants were required to adhere to a complex regimen of zidovudine, zalcitabine and didanosine, or their matching placebos. DESIGN: Between October 1992 and January 1994, study sites were selected at random, and a 1-week period was designated during which study participants attending routine clinic visits provided a blood sample and dosing history. Participants were not informed of the purpose of the substudy. MEASUREMENTS: Adherence was assessed using plasma drug concentrations and defined by the presence of detectable drug in a plasma sample obtained within a specified analysis window. RESULTS: Of 722 plasma samples analyzed, approximately 75% contained detectable concentrations of the assigned drugs and 5-14.5% contained no detectable drugs. Approximately 7 and 13% of samples from participants assigned to monotherapy arms contained non-prescribed dideoxynucleosides, and 14 and 19% assigned to combination therapies contained only one drug. CONCLUSIONS: Various non-adherence behaviors were observed, including patterns of underdosing and taking non-prescribed drugs. Non-adherence was moderate but uniform amongst the treatment groups and may have contributed to a marginal reduction in the power of the primary intent-to-treat analysis to detect differences in efficacy amongst the assigned treatments.

Pancreatitis with didanosine and tenofovir disoproxil fumarate [corrected].

Pancreatitis occurs in up to 7% of patients infected with human immunodeficiency virus who are treated with standard doses of didanosine. Tenofovir disoproxil fumarate increases the plasma levels of didanosine and, thus, the combination of these agents may increase the risk of pancreatitis. Four cases of pancreatitis that occurred during administration of this drug combination are examined, including 1 that resulted in death.

Food-induced reduction in bioavailability of didanosine.

The effect of food on the pharmacokinetics of didanosine was evaluated in an open two-way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration-time curves (AUC0-infinity) were 3902 (1316) and 2083 (922) hr.ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact didanosine when didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0-infinity, and %UR were significantly lower for subjects who received didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half-life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0-infinity and %UR, was reduced significantly in the presence of food. It is recommended that didanosine be administered under fasting conditions.

Pharmacokinetics of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine in patients with severe human immunodeficiency virus infection.

This article describes the pharmacokinetics of 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) as determined during phase I clinical trials in patients with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome-related complex. Drug levels were determined by HPLC in plasma, cerebrospinal fluid, and urine after administration of the drugs either intravenously or as an oral liquid given with antacid. ddA was metabolized rapidly and quantitatively to ddI to such an extent that ddA was undetectable in the plasma even during continuous intravenous administration of ddA. The plasma kinetics of ddI were generally monoexponential and were characterized by a half-life of 38 minutes. This probably does not accurately reflect the kinetics of the active species of ddI, which appears to be 2',3'-dideoxyadenosine triphosphate, formed intracellularly. Oral bioavailability was 38% for oral liquid given with antacid. The total body clearance averaged 1.00 L/kg/hr, with a volume of distribution of 1.01 L/kg. Approximately 36% of the intravenous dose could be recovered unchanged in the urine. The level of ddI in the cerebrospinal fluid 1 hour after drug infusion averaged 21% of that of the simultaneous plasma level. It is concluded that ddI has pharmacokinetic properties that are amenable to its clinical use.

Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex.

The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials.

Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications.

2',3'-Dideoxyinosine (ddI) has shown activity against human immunodeficiency virus in phase I clinical trials. The drug is rapidly degraded by acid, however, thus raising questions as to the efficiency and reproducibility of its absorption after oral administration. This investigation studies the bioavailability of several oral dosage forms of ddI. When ddI was given to fasting patients as an oral solution with antacid, the bioavailability was 41% +/- 7% (mean +/- SEM). However, when given as buffered tablets, the bioavailability was considerably less (25% +/- 5%). The bioavailability increased slightly when the tablets were given with supplemental antacid (36% +/- 6%). Two enteric-coated preparations had reasonable bioavailability (36% +/- 5% and 26% +/- 5%), but the peak plasma level was much lower and occurred at a much later time than with the oral solution. When ddI was given as a premeasured powder containing sucrose and buffer to be reconstituted by the patient (the "sachet" preparation), the bioavailability was 29% +/- 6%. This was similar to that of the oral solution for this particular group of patients (30% +/- 7%). However, the bioavailability of the sachet was only 17% +/- 4% when administered with food. When the sachet was given to patients receiving ranitidine, no consistent change in bioavailability was noted. Also, no change in ddI pharmacokinetics was noted in patients receiving ganciclovir.

Disposition of didanosine in HIV-seropositive patients with normal renal function or chronic renal failure: influence of hemodialysis and continuous ambulatory peritoneal dialysis.

OBJECTIVE: To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic kidney failure. METHODS: Three groups of patients with human immunodeficiency virus (HIV) infection were studied: group I, six men with normal kidney function (creatinine clearance > 90 ml/min/1.73 m2); group II, six men with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD); and group III, four men and two women with chronic renal failure receiving hemodialysis three times a week. A 300 mg dose of didanosine was administered orally and intravenously according to a two-period randomized crossover design. Patients in group III were studied between hemodialysis sessions during the crossover periods. In addition, patients in group III were studied in a third period after administration of a 300 mg oral dose of didanosine 4 hours before hemodialysis. RESULTS: After intravenous administration in group I, the mean (+/-SD) total clearance (CLT) was 13.0 +/- 1.6 ml/min/kg and the elimination half-life (t 1/2) was 1.56 +/- 0.43 hour. In groups II and III, the CLT decreased significantly to 3.4 +/- 1.2 and 3.2 +/- 1.2 ml/min/kg, respectively, whereas the t1/2 increased to 3.60 +/- 0.82 hours and 3.11 +/- 0.88 hours, respectively. The absolute bioavailability of didanosine in groups I, II, and III was 42% +/- 12%, 52% +/- 6%, and 38% +/- 11%, respectively, and did not differ significantly. CAPD had little effect on the removal of didanosine, whereas approximately 30% of the drug present in the body at the start of dialysis was eliminated by an average 3-hour dialysis session. CONCLUSION: The clearance of didanosine is impaired in patients with chronic renal failure. To compensate, the dose and schedule of administration should be adjusted. It is recommended that one-fourth of the total daily dose of didanosine be administered once a day in this patient population.

Pharmacokinetics of dideoxyinosine in pigtailed macaques (Macaca nemestrina) after intravenous and subcutaneous administration.

Four macaques (Macaca nemestrina; 1 female and 3 males) were administered dideoxyinosine (DDI) at three dose levels (3.2 mg/kg i.v., 10 mg/kg i.v., and 20 mg/kg s.c.). Blood and urine samples were collected during 6-8 h and 24 h after drug administration, respectively. The mean plasma clearance (16.7 +/- 4.9 ml/min/kg), steady-state volume of distribution (1.5 +/- 0.4 L/kg), and terminal plasma half-life (96.8 +/- 7.5 min) did not differ significantly between the two i.v. doses. DDI was eliminated from the body primarily by excretion of the unchanged drug in the urine (74%). The absorption of DDI from the subcutaneous site was complete (bioavailability of 0.91 +/- 0.13) and rapid, with peak plasma concentration obtained at 30 min.

Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection.

BACKGROUND: Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine. METHODS: Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10(9) cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. RESULTS: Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months; range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by > or = .05 x 10(9) cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration. CONCLUSIONS: Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment.

Pharmacokinetic optimisation of antiretroviral therapy in patients with HIV infection.

More than 7 years after the introduction of zidovudine for treatment of HIV infection, little use has been made of the pharmacokinetic properties of this or any of the subsequently approved antiretroviral agents to optimise therapy. This is partly because of the limits of technologies developed to measure clinically relevant forms and concentrations of these drugs, and partly because the clinical community has been slow to recognise the potential benefits of pharmacokinetic optimisation of nucleoside analogue therapy in any disease. Nonetheless, for some of these agents, progress in understanding the relationship between pharmacokinetics and pharmacodynamics has been made. With zidovudine, for example, even though plasma concentrations have little clinical utility, evidence suggests that concentrations of active phosphorylated forms of zidovudine inside target cells are related to disease progression and toxicity. Furthermore, a decreased ability to phosphorylate zidovudine might be a prerequisite for the emergence of zidovudine-resistant HIV strains. Measurements of phosphorylated zidovudine inside cells similarly suggest that 100 mg of oral zidovudine every 8 hours approximates the optimal initial dosage regimen in asymptomatic patients. Increased plasma didanosine concentrations have been associated with several measures of clinical improvement in patients, and may be associated with an increased risk of toxicity as well. For zalcitabine and stavudine, however, the picture is much less clear. Their pharmacokinetic and pharmacodynamic relationships have not been studied in patients. Furthermore, there is insufficient data on the effects of age, gender, race and concurrent underlying conditions on the pharmacokinetics of all of these agents. Mounting evidence suggests that monitoring of these compounds could lead to individually optimised intervention strategies. Given the marginal benefits of therapy with these agents, their proven toxic effects and the lack of proven alternatives, it is critical that the clinical community strive to make the most effective use of these agents in the treatment of their patients.

Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team.

The effect of food on didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in similar areas under the concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8 microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3 liters/hr/m2) were similar, but these values in children are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of didanosine was highly variable in children but similar in the presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected children.