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Biomedical subjects

F Aweeka

Publications and source records attributed to F Aweeka.

13 recordsLinked to original sources
PubMed2001

Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401.

UNLABELLED: The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects. DESIGN: A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. RESULTS: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p =.001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p =.129 and p =.0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. CONCLUSIONS: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.

Adult↗
PubMed2001

Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study.

A small-scale clinical investigation was done to quantify the penetration of stavudine (D4T) into cerebrospinal fluid (CSF). A model-based analysis estimates the steady-state ratio of AUCs of CSF and plasma concentrations (R(AUC)) to be 0.270, and the mean residence time of drug in the CSF to be 7.04 h. The analysis illustrates the advantages of a causal (scientific, predictive) model-based approach to analysis over a noncausal (empirical, descriptive) approach when the data, as here, demonstrate certain problematic features commonly encountered in clinical data, namely (i) few subjects, (ii) sparse sampling, (iii) repeated measures, (iv) imbalance, and (v) individual design variation. These features generally require special attention in data analysis. The causal-model-based analysis deals with features (i) and (ii), both of which reduce efficiency, by combining data from different studies and adding subject-matter prior information. It deals with features (iii)--(v), all of which prevent 'averaging' individual data points directly, first, by adjusting in the model for interindividual data differences due to design differences, secondly, by explicitly differentiating between interpatient, interoccasion, and measurement error variation, and lastly, by defining a scientifically meaningful estimand (R(AUC)) that is independent of design.

Anti-HIV Agents↗
PubMed2001

Pharmacokinetics and pharmacodynamics of thalidomide in HIV patients treated for oral aphthous ulcers: ACTG protocol 251. AIDS Clinical Trials Group.

Thalidomide has increasing clinical benefits, including the healing of aphthous ulcers in patients with HIV. Unfortunately, pharmacological information addressing the pharmacokinetics (PK) of this compound in HIV patients is limited. Concern exists as to whether thalidomide may alter its own metabolism owing to in vitro data previously reported. Furthermore, no information is available defining the relationship between drug exposure and clinical response. This study evaluated the PK and pharmacodynamics (PD) of thalidomide in patients enrolled in AIDS Clinical Trials Group Protocol 251. Study patients had HIV infection and oral aphthous ulcers of at least 2 weeks'duration. Pharmacologic studies were completed in those subjects randomized to receive active thalidomide at a dose of 200 mg daily for the 4-week study period. PK studies involving serial sampling were carried out in 7 subjects following multiple dosing during study weeks 1 and 4. In addition, trough measurements were done in 20 subjects during each of the 4 study weeks to explore the relationship between time-averaged trough values and extent of clinical response. All samples were analyzed using a validated HPLC method, and parameters were determined using noncompartmental PK analysis. Thalidomide oral clearance averaged 0.14 +/- 0.08 and 0.12 +/- 0.05 l/h/kg on weeks 1 and 4 (p = 0.72), while the terminal elimination half-life averaged 5.7 +/- 1.5 and 7.3 +/- 1.7 hours (p = 0.12). The median time-averaged trough value for subjects deemed complete responders was 0.60, while the median value for noncomplete responders was 0.54. Adjusting for baseline CD4 count and initial index ulcer area, no significant effects were observed of increased thalidomide levels on response. In summary, this study provides steady-state PK data in HIV patients managed with thalidomide and suggests negligible effect of chronic dosing on drug clearance (comparing results from weeks 1 and 4). Furthermore, variable trough measurements between patients do not directly influence the effectiveness of thalidomide for oral aphthous ulcers.

Adult↗
PubMed2000

The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function.

AIMS: To assess whether renal impairment influences the pharmacokinetics of ziprasidone, and to determine whether ziprasidone is cleared via haemodialysis. METHODS: Thirty-nine subjects with varying degrees of renal impairment were enrolled into an open-label, multicentre, multiple-dose study and assigned to four groups according to their renal function: normal (group 1, creatinine clearance > 70 ml min(-1); mildly impaired (group 2, creatinine clearance 30-60 ml min(-1); moderately impaired (group 3, creatinine clearance 10-29 ml min(-1), and severely impaired (group 4, requiring haemodialysis three times-a-week). Subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 7 days and a single 20 mg dose on the morning of day 8. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 8 (haemodialysis day for subjects with severe renal impairment). Additional samples were collected from subjects with severe renal impairment on day 7 (nonhaemodialysis day). RESULTS: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0, 12 h), Cmax, tmax) of ziprasidone among subjects with normal renal function and those with mild, moderate and severe renal impairment. The AUC(0,12 h) and Cmax in subjects with mildly impaired renal function were statistically significantly greater than in those with moderately impaired renal function (P = 0.0163-0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml(-1) h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 47, 61, 41 and 50 ng ml(-1) and corresponding mean tmax values were 5, 6, 5 and 5 h. On day 8 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax, lambda(z), Fb) of ziprasidone among subjects with normal renal function and those with moderate or severe renal impairment. The AUC(0,12 h) in subjects with mild renal impairment was statistically significantly greater than those in the other three groups (P = 0.0025-0.0221), but this was not considered clinically significant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml(-1) h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 68, 93, 54 and 70 ng ml(-1), corresponding mean tmax values were 4, 5, 4 and 5 h and corresponding mean lambda(z) were 0.14, 0.11, 0.14 and 0.17 h(-1). The mean percentage Fb was 99.84-99.88% across all groups and the mean t(1/2),z ranged from 4.2 to 6.4 h. Comparison of the mean AUC(0,12 h) and Cmax values in subjects with severe renal impairment on day 7 with those on day 8 suggested that haemodialysis does not have a clinically significant effect on the pharmacokinetics of ziprasidone. CONCLUSIONS: The findings of this study indicate that mild-to-moderate impairment of renal function does not result in clinically significant alteration of ziprasidone pharmacokinetics and therefore does not necessitate dose adjustment.

Adolescent↗
PubMed1999

Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection.

OBJECTIVES: To compare the kinetics and magnitude of HIV-1 RNA responses to antiretroviral therapy (ART) in the cerebrospinal fluid (CSF) and plasma. DESIGN: Repeated lumbar punctures (LPs) were performed after the initiation or change in ART in 15 HIV-1-infected subjects, with the focus on two phases of response: an acute phase within the first 11 days, for which crude estimates of viral RNA half-lives and decay rates were derived and CSF:plasma relative decay ratios quantitatively analysed; and a longer-term phase beyond 4 weeks that was descriptively assessed. RESULTS: In 13 subjects studied during the acute phase, the crude HIV-1 RNA half-life was longer (median 2.0 compared with 1.9 days), the decay rate slower (median 0.13 compared with 0.16 log10 copies/day) and, most notably, the variability greater (intraquartile range of half-life 1.8-4.3 compared with 1.7-2.1 days) in the CSF than in the plasma. A slower decay in the CSF correlated with lower initial blood CD4 T lymphocyte counts (P = 0.001). Seven of 11 subjects studied at 4 weeks or later, including some with slower acute-phase CSF responses, showed greater or more durable viral suppression in the CSF. CONCLUSION: Divergent acute-phase viral kinetics in the CSF and plasma, and proportionally greater long-term decrements in CSF HIV-1 RNA in slow early-responders or poor overall plasma responders indicate variable compartmentalization of CSF infection, consistent with a model of two prototypes of CSF infection: short-lived, transitory infection that predominates in early HIV-1 infection and longer-lived, more autonomous CSF infection predominating in late HIV-1 infection. Additional studies will be needed to define more precisely the acute and longer-term CSF kinetics in different clinical settings and to assess this model.

AIDS Dementia Complex↗
PubMed1999

Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex.

OBJECTIVE: To assess the penetration of the HIV-1 protease inhibitor, nelfinavir, into cerebrospinal fluid (CSF). DESIGN: Nelfinavir, a commonly used HIV-1 protease inhibitor (PI), is highly effective for reducing plasma viral load. It is deployed clinically in combination with other antiretroviral agents, including nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Despite its potency based on plasma HIV-1 RNA results, its effectiveness in reducing HIV-1 RNA levels (i.e., viral load) in the central nervous system (CNS) is less certain. We sampled the CSF as a surrogate for brain because this fluid also is separated from the blood by a barrier to free diffusion, the blood-CSF barrier (BCB), which shares properties with the blood-brain barrier (BBB). These studies of nelfinavir CSF pharmacokinetics exploited the multiple CSF samples derived from individual study subjects who were enrolled in studies the primary objective of which was to compare viral kinetics in CSF and blood in response to antiviral therapy. METHODS: Six study subjects, four with and two without AIDS dementia complex, underwent multiple lumbar punctures (LP). Intervals of CSF sampling after drug dosing were varied (from 0.48 hours to 10.3 hours after nelfinavir administration) to quantitate nelfinavir concentrations throughout the steady-state dosing interval. In four study subjects, CSF sampling was accompanied by assessment of nelfinavir levels in plasma before and after LP, whereas in the other two subjects, a single plasma sample was obtained before or after the LP. In total, 25 CSF samples were analyzed. Nelfinavir concentrations in CSF and plasma were determined using an high-performance liquid chromatography (HPLC) method with a limit of quantitation of 25 and 50 ng/ml, respectively. RESULTS: Plasma concentrations before and after LP averaged 2420+/-1365 ng/ml and 2528+/-1132 ng/ml, respectively. Nelfinavir was not detected in any of the CSF samples and levels >25 ng/ml were not present in the CSF. Thus, standard therapy with nelfinavir does not result in CSF drug concentrations at or exceeding the IC95 level for most HIV-1 isolates. However, study subjects with high CSF viral loads experienced a marked reduction in the context of the combination-drug regimen including nelfinavir with two subjects showing a comparable CSF response with that in plasma. CONCLUSIONS: Nelfinavir does not appreciably penetrate into the CSF. The clinical importance of this observation is not certain, in that in four study subjects who initiated nelfinavir in combination with other antiretroviral therapy, a comparable degree of viral suppression was obtained in both the CSF and the blood when sampled 4 weeks or later after initiating therapy.

AIDS Dementia Complex↗
PubMed1999

High-performance liquid chromatographic determination of ribavirin in whole blood to assess disposition in erythrocytes.

Ribavirin is an antiviral agent used in the treatment of chronic hepatitis C virus infection. One of the limitations associated with the use of ribavirin is a reversible anemia caused by its accumulation in erythrocytes. Therefore, it is of interest to determine ribavirin levels in erythrocytes, as well as in plasma, as these measurements may be predictive of hematotoxicity. In the present study, we describe a high-performance liquid chromatographic (HPLC) assay for ribavirin in whole blood to estimate concentrations of free ribavirin and phosphorylated anabolites in erythrocytes. Since ribavirin exists primarily as phosphorylated anabolites (mono-, di-, and triphosphates) in erythrocytes, whole-blood extracts were initially dephosphorylated with acid phosphatase. The enzyme-treated samples were subjected to phenyl boronic acid column extraction for cleanup. The purified fraction was analyzed by reversed-phase HPLC, which was optimized for determination of ribavirin levels in whole blood. The recoveries of ribavirin from whole blood ranged from 63.1 to 90.7% at concentrations ranging from 1.67 to 40.0 microM. Intra- and interassay variations estimated at these concentrations were 3.2 to 10.4 and 4.7 to 11.7%, respectively. This method was used to quantitate ribavirin in samples both treated and untreated with acid phosphatase to estimate the extent of intracellular phosphorylation in erythrocytes. The method was also used to evaluate the effects of dipyridamole, a nucleoside transporter inhibitor, on ribavirin disposition in erythrocytes in in vitro experiments.

Acid Phosphatase↗
PubMed1999

Altered pharmacokinetics of indinavir by a novel nonnucleoside reverse transcriptase inhibitor (HBY-097): a pharmacokinetic evaluation in HIV-positive patients.

HBY-097 (HBY), an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI), and indinavir (IDV) share a common metabolic pathway, cytochrome P4503A4 (CYP3A4), and may clinically be used together as well as with zidovudine (ZDV). Thus, the potential pharmacokinetic (PK) interaction between these drugs was evaluated. HBY (500 mg Q8H), IDV (800 mg Q8H), and ZDV (200 mg Q8H) were given to 8 HIV-infected subjects. Serial plasma samples were collected at baseline (ZDV and IDV alone) and day 11 (all 3 drugs) to determine PK parameters using noncompartmental analysis. PK parameters for ZDV in the presence and absence of HBY were not appreciably different. However, both the maximum (Cmax) and minimum (Cmin) concentrations of IDV were significantly reduced, from a mean of 7514 +/- 1636 and 146 +/- 81 mcg/L to 4725 +/- 2494 mcg/L and 54 +/- 24 mcg/L (p < .05) after addition of HBY. Furthermore, apparent clearance (CL/F) of IDV before and after 11 days of concomitant HBY administration was significantly higher, from 0.69 +/- 0.14 to 1.94 +/- 0.63 L/h/kg (p < .05) with an associated reduction in area under the curve (AUC0-8) from 16,034 +/- 4903 to 6134 +/- 2701 mg/L/h (p < .05). The increase in IDV CL/F is consistent with the observed metabolic induction effects of other NNRTIs. The results of this trial showed that HBY significantly alters the pharmacokinetic parameters of IDV at the dose studied.

Adult↗
PubMed1996

Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients.

OBJECTIVE: To determine some of the factors influencing the time to progression of cytomegalovirus (CMV) retinitis among HIV-infected patients being treated with foscarnet. DESIGN: A retrospective analysis of two open-label Phase I/II studies in multiple university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of the patients in the databases examined, 31 had adequate pharmacokinetic information and 29 had information on outcome and the other patient covariates. INTERVENTION: After induction therapy with foscarnet at a dose of 60 mg/kg three times daily was completed, patients had maintenance therapy with 60-120 mg/kg foscarnet once daily. Doses were subsequently adjusted for changed estimated creatinine clearance. MEASUREMENTS: The measured endpoint was time to progression of CMV retinitis. The independent variables examined to determine influence on time to progression included mean peak foscarnet concentration, mean area under the concentration-time curve (AUC) for foscarnet, the positive or negative outcome of a baseline blood culture for CMV, the initial CD4 cell count for a patient and the peak CD4 cell count observed during maintenance therapy. RESULTS: A wide range (-10-fold) of foscarnet AUC was observed, even though only a fourfold dose range was employed, and doses were altered for changing estimated creatinine clearance. In a multivariate Cox model, only AUC and the status of the baseline CMV blood culture significantly affected the time to progression of the retinitis. CONCLUSION: The AUC produced by a dose of foscarnet has a wide interindividual range. The AUC of foscarnet significantly altered time to progression of the retinitis. However, patients with positive baseline CMV blood cultures had a significantly more shallow dose-response curve. This indicates that the added risk of nephrotoxicity which is present with aggressive foscarnet dosing might be best borne by the subgroup of patients with a positive CMV blood culture at baseline.

Analysis of Variance↗
PubMed1989

Pharmacokinetics of intermittently administered intravenous foscarnet in the treatment of acquired immunodeficiency syndrome patients with serious cytomegalovirus retinitis.

Foscarnet has been shown to be active in vitro against the human immunodeficiency virus and all human herpesviruses including cytomegalovirus (CMV). A pharmacokinetic study was carried out as part of a clinical trial designed to evaluate the safety and efficacy of intermittently administered intravenous foscarnet for the treatment of CMV retinitis. Eight patients with acquired immunodeficiency syndrome and serious CMV retinitis received 2-h intravenous infusions of foscarnet at a dosage of 60 mg/kg of body weight every 8 h for 14 days. Serial plasma samples were collected on days 3 and 14 of therapy, and foscarnet concentrations were determined by high-pressure liquid chromatography. On day 3 of therapy, the mean (+/- standard deviation) peak and trough levels in plasma were 509 (200) and 98 (29) microM, respectively, while on day 14 levels were 495 (149) and 126 (59) microM. The mean clearance in plasma on days 3 and 14 were 1.9 (0.6) and 1.7 (0.9) ml/min per kg, respectively. On day 14, the mean half-life was 4.5 (1.2) h and the volume of distribution was 0.74 (0.60) liter/kg. As the half-life and the clearance of foscarnet in plasma correlated with changes in renal function, dosage adjustments must be made for patients with decreased renal function.

Acquired Immunodeficiency Syndrome↗