ABSTRACT
Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.
Subject(s)
Black or African American/genetics , Calcineurin Inhibitors/administration & dosage , Cytochrome P-450 CYP3A/genetics , Drug Dosage Calculations , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Pharmacogenomic Variants , Tacrolimus/administration & dosage , Transplant Recipients , Adolescent , Adult , Aged , Calcineurin Inhibitors/adverse effects , Calcineurin Inhibitors/pharmacokinetics , Canada/epidemiology , Cytochrome P-450 CYP3A/metabolism , Female , Gene Frequency , Genotype , Graft Rejection/ethnology , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft Survival/drug effects , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation/adverse effects , Male , Metabolic Clearance Rate/genetics , Middle Aged , Models, Genetic , Pharmacogenetics , Pharmacogenomic Testing , Phenotype , Tacrolimus/adverse effects , Tacrolimus/pharmacokinetics , Treatment Outcome , United States/epidemiology , Young AdultABSTRACT
BACKGROUND: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition. METHODS: Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development. RESULTS: The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m(-2) min(-1) and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. CONCLUSION: Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m(-2) min(-1) and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Deoxycytidine/analogs & derivatives , Membrane Transport Proteins/genetics , Neoplasms/genetics , Neoplasms/metabolism , 5'-Nucleotidase/genetics , 5'-Nucleotidase/metabolism , Adult , Aged , Aged, 80 and over , Alleles , Antimetabolites, Antineoplastic/blood , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Female , Genotype , Humans , Infusions, Intravenous , Leukocytes, Mononuclear/metabolism , Male , Membrane Transport Proteins/metabolism , Middle Aged , Neoplasms/blood , Neoplasms/drug therapy , Young Adult , GemcitabineABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. METHODS: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model. RESULTS AND DISCUSSION: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume V(d)/F = 50·1 L (1·29 as high for males), absorption rate constant K(aA) = 0·391/h, K(aB,C,D) = 2·70/h, relative bioavailability F(A) = 0·468, F(B,C,D) = 1, lag time in the absorption phase T(lag) = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, V(d) /F and K(a) by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%. WHAT IS NEW AND CONCLUSION: Gender was associated with changes in CL/F and V(d) /F whereas the pharmaceutical formulation was associated with changes in F and altered the K(a) . The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.
Subject(s)
Antibiotics, Antitubercular/pharmacokinetics , Models, Biological , Rifampin/pharmacokinetics , Tuberculosis/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibiotics, Antitubercular/administration & dosage , Antibiotics, Antitubercular/therapeutic use , Biological Availability , Female , Humans , Male , Mexico , Middle Aged , Nonlinear Dynamics , Prospective Studies , Rifampin/administration & dosage , Rifampin/therapeutic use , Sex Factors , Tissue Distribution , Young AdultABSTRACT
Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half-life in patients at steady state have not been determined. We developed an intravenous, stable-labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety-two patients received a 100-mg infusion of SL-carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography-mass spectrometry, and concentration-time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half-life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.
Subject(s)
Anticonvulsants/administration & dosage , Anticonvulsants/pharmacokinetics , Carbamazepine/administration & dosage , Carbamazepine/pharmacokinetics , Epilepsy/drug therapy , Epilepsy/metabolism , Administration, Oral , Adult , Anticonvulsants/blood , Biological Availability , Carbamazepine/blood , Chemistry, Pharmaceutical , Epilepsy/blood , Female , Half-Life , Humans , Infusions, Intravenous/methods , Male , Sex FactorsABSTRACT
OBJECTIVES: To determine a population pharmacokinetic model of the antihelmintic drug, albendazole, and identify the factors influencing the pharmacokinetic parameters in patients with neurocysticercosis. METHODS: A prospective study was performed in 90 patients receiving 30 mg/kg/day of albendazole for 8 days. Blood samples were collected at steady state. Plasma concentrations of albendazole sulfoxide, the main active metabolite of albendazole, were determined by HPLC. The population pharmacokinetics analysis was performed using non-linear mixed-effect modeling (NONMEM). A one-compartment model with first order absorption and elimination was used. RESULTS: Body weight was included empirically on CL/F and V/F using an allometric relationship. Although none of the investigated covariates had a significant influence on the pharmacokinetic parameters of albendazole, the final model identified two subpopulations on the bioavailability parameter. One subpopulation comprising of 27% of the total population had a bioavailability of 28%, with the remaining subpopulation defined to have complete bioavailability. The CL/F and V/F for a standard 70 kg individual was determined to be 51.6 l/h and 4560 l, respectively. Interindividual variability in CL/F was 32%; the residual unexplained variability was 32%. CONCLUSIONS: The considerable variability reported in albendazole pharmacokinetics and plasma concentrations is likely due to issues related to bioavailability. With one-fourth of the population absorbing as little as 30% of the drug relative to others, low drug exposures might be responsible for treatment failures. Therapeutic drug monitoring may be warranted to optimize the eradication of the infecting parasite.
Subject(s)
Albendazole/pharmacokinetics , Anthelmintics/pharmacokinetics , Models, Biological , Neurocysticercosis/drug therapy , Adolescent , Adult , Aged , Albendazole/analogs & derivatives , Albendazole/therapeutic use , Anthelmintics/therapeutic use , Biological Availability , Chromatography, High Pressure Liquid , Drug Monitoring/methods , Female , Humans , Male , Middle Aged , Nonlinear Dynamics , Prospective Studies , Young AdultABSTRACT
BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2-3 weeks.
Subject(s)
Anticonvulsants/pharmacokinetics , Epilepsy/drug therapy , Phenytoin/pharmacokinetics , Administration, Oral , Adult , Age Factors , Aged , Aged, 80 and over , Aging/physiology , Anticonvulsants/administration & dosage , Anticonvulsants/blood , Drug Administration Schedule , Epilepsy/prevention & control , Female , Gas Chromatography-Mass Spectrometry , Humans , Injections, Intramuscular , Injections, Intravenous , Male , Metabolic Clearance Rate/physiology , Middle Aged , Phenytoin/administration & dosage , Phenytoin/blood , Sex FactorsABSTRACT
Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and > or = 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach < 400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA < 400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.
Subject(s)
Benzoxazines/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Nelfinavir/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Administration, Oral , Adolescent , Alkynes , Area Under Curve , Benzoxazines/administration & dosage , Cyclopropanes , Drug Therapy, Combination , HIV Infections/metabolism , HIV Infections/virology , HIV Protease Inhibitors/administration & dosage , Humans , Metabolic Clearance Rate , Nelfinavir/administration & dosage , RNA, Viral/blood , Reverse Transcriptase Inhibitors/administration & dosage , Treatment Outcome , United States , Virus Replication/drug effectsABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacokinetics , Cytomegalovirus Infections/drug therapy , Ganciclovir/analogs & derivatives , Ganciclovir/pharmacokinetics , Administration, Oral , Antiviral Agents/blood , Antiviral Agents/therapeutic use , Area Under Curve , Body Weight , Chromatography, High Pressure Liquid , Female , Ganciclovir/blood , Ganciclovir/therapeutic use , Humans , Infant , Infant, Newborn , Infant, Newborn, Diseases/drug therapy , Injections, Intravenous , Male , Tandem Mass Spectrometry , ValganciclovirABSTRACT
OBJECTIVES: To evaluate the pharmacokinetics, tolerance, safety and antiviral activity of the HIV protease inhibitor, saquinavir, formulated as soft gelatin capsules (SQV-SGC), given in combination with nucleoside antiretroviral agents (NRTIs) with or without nelfinavir in HIV-infected children. METHODS: This was an open label study of HIV-infected children ages 3 to 16 years, conducted in two parts. In Part 1 of the study 14 children were treated orally with SQV-SGC (initially given in three 33-mg/kg doses daily; dosage adjusted to 50 mg/kg three times daily based on initial pharmacokinetics) and two NRTIs. Addition of nelfinavir was permitted for children who did not achieve a predetermined steady state target plasma saquinavir exposure. In Part 2 a new group of 13 children received SQV-SGC (33 mg/kg three times daily) in combination with nelfinavir and one or two NRTIs. Pharmacokinetics were assessed after the first dose and 4 weeks into treatment (steady state). Patients were treated for 72 and 48 weeks in Parts 1 and 2, respectively. RESULTS: Most adverse events were mild; the most commonly reported were diarrhea, abdominal discomfort and headache. Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment. There were no deaths or serious adverse events attributed to the study medication. Steady state saquinavir area under the plasma concentration vs. time curves (AUC24) were 6,210 and 11,010 ng/h/ml for Parts 1 and 2, respectively. Compared with baseline measurements median changes in plasma HIV RNA concentrations were -2.12 log10 copies/ml [5 of 14 (36%) with HIV RNA <50 copies/ml) (Week 72)] and -2.58 log10 copies/ml [8 of 13 (62%) <50 copies/ml) (Week 48)] in Parts 1 and 2, respectively. The median changes in CD4+ lymphocyte count were +292 and +154 cells/microl for Parts 1 and 2, respectively. Genotypic resistance assays revealed a low frequency of saquinavir-associated resistance mutations after 48 weeks of therapy, with only 2 of 27 children having substitutions at positions 48V and/or 90M. CONCLUSIONS: Combination therapy with SQV-SGC was well-tolerated and safe in HIV-infected children, and antiviral activity was observed. Saquinavir plasma concentrations were lower than expected, particularly for Part 1 (SQV-SGC plus NRTIs), but addition of nelfinavir increased saquinavir exposures.
Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Saquinavir/therapeutic use , Administration, Oral , Adolescent , Antiretroviral Therapy, Highly Active/methods , Capsules , Child , Child, Preschool , Female , Gelatin , HIV Infections/diagnosis , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , Humans , Male , Nelfinavir/therapeutic use , Prognosis , Reverse Transcriptase Inhibitors/therapeutic use , Saquinavir/administration & dosage , Saquinavir/adverse effectsABSTRACT
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.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Indinavir/therapeutic use , Lamivudine/therapeutic use , Zidovudine/therapeutic use , Adult , Algorithms , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Area Under Curve , Drug Therapy, Combination , Female , HIV Infections/virology , Half-Life , Humans , Indinavir/administration & dosage , Indinavir/pharmacokinetics , Lamivudine/administration & dosage , Lamivudine/pharmacokinetics , Male , Middle Aged , Patient Compliance , Zidovudine/administration & dosage , Zidovudine/pharmacokineticsABSTRACT
Tacrolimus is an immunosuppressant commonly used in the prevention of graft-versus-host disease (GVHD) following allogeneic HCT. Unfortunately, the use of tacrolimus is associated with variable immunosuppression and toxicity. The purpose of this study was to describe tacrolimus population pharmacokinetic parameters, to identify relationships between clinical covariates and pharmacokinetic estimates, and to develop a model to predict tacrolimus clearance in HCT patients. Steady-state whole blood tacrolimus concentrations (n = 1625) obtained during intravenous and oral therapy were analyzed in 122 patients. Population clearance (CL) was 5.22 l/h and bioavailability (F) was 0.28. The influence of clinical covariates on population estimates of CL and F of tacrolimus were tested with nonlinear mixed effects models (NONMEM). CL was significantly reduced by elevations in total bilirubin 2.0-9.9 mg/dl (CL * 0.797), bilirubin > or = 10 mg/dl (CL * 0.581), serum creatinine > or = 2 mg/dl (CL * 0.587), grade III/IV graft-versus-host disease (CL * 0.814) and veno-occlusive disease (CL 0.814). No covariates were predictive of oral F. The interindividual variabilities in CL and F were 33% and 44%, respectively. Residual variability was 27.5% and 16.8% at tacrolimus concentrations of 10 microg/l and 20 microg/l, respectively. These models may be used to predict tacrolimus clearance and doses in adult patients following HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/pharmacokinetics , Tacrolimus/pharmacokinetics , Administration, Oral , Adolescent , Adult , Biological Availability , Creatinine/blood , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/blood , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hepatic Veno-Occlusive Disease/etiology , Humans , Hyperbilirubinemia/metabolism , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Infusions, Intravenous , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Patient Compliance , Retrospective Studies , Tacrolimus/administration & dosage , Tacrolimus/blood , Transplantation, Homologous/adverse effectsABSTRACT
OBJECTIVE: To quantify unbound indinavir concentrations and characterize indinavir plasma protein binding in HIV-infected adults. DESIGN: Pharmacokinetic study in antiretroviral-naive, HIV-infected persons with CD4 T lymphocytes > 100 x 10(6) cells/L and HIV-RNA in plasma >5000 copies/ml at baseline who were participating in an open-label study of zidovudine, lamivudine and indinavir therapy. METHODS: Eight men underwent 8 h intensive pharmacokinetic studies for indinavir on two occasions 6 months apart. Unbound indinavir was separated by ultra-filtration, and unbound and total concentrations were quantified by a validated high-performance liquid chromatography method. RESULTS: Overall indinavir protein binding was 61+/-6%, with a range among the profiles of 54 to 70%. Indinavir binding was higher at the 8 h post-dose concentration compared with the 1 h post-dose concentration (66 versus 57%, P = 0.0006). CONCLUSIONS: The mean 61% protein binding for indinavir in these HIV-infected persons is similar to the in vitro report of 60%. However, the fraction bound was concentration-dependent, and considerable variability in binding was present among patients. Quantification of unbound protease inhibitor concentrations opens new avenues of research to advance our understanding of the pharmacologically-relevant moieties of antiretroviral agents and thereby the pharmacotherapy of HIV infection.
Subject(s)
Blood Proteins/metabolism , HIV Infections/drug therapy , HIV-1 , Indinavir/pharmacokinetics , Adult , HIV Protease Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Protein BindingABSTRACT
OBJECTIVE: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. DESIGN: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. METHODS: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. RESULTS: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. CONCLUSION: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.
Subject(s)
Anti-HIV Agents/therapeutic use , Cytidine Triphosphate/therapeutic use , HIV Infections/drug therapy , HIV , Lamivudine/therapeutic use , Thymine Nucleotides/therapeutic use , Zidovudine/therapeutic use , Adolescent , Adult , Aged , Anti-HIV Agents/pharmacokinetics , CD4 Lymphocyte Count , Cytidine Triphosphate/analogs & derivatives , Cytidine Triphosphate/pharmacokinetics , Dideoxynucleotides , Dose-Response Relationship, Drug , Drug Therapy, Combination , HIV Infections/metabolism , HIV Infections/virology , Humans , Lamivudine/analogs & derivatives , Lamivudine/pharmacokinetics , Leukocytes, Mononuclear/metabolism , Middle Aged , Prospective Studies , RNA, Viral/analysis , Regression Analysis , Reverse Transcriptase Inhibitors/therapeutic use , Thymine Nucleotides/pharmacokinetics , Zidovudine/analogs & derivatives , Zidovudine/pharmacokineticsABSTRACT
STUDY OBJECTIVE: To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1). DESIGN: Open-label observational study. SETTING: University-affiliated teaching hospital and research center. PATIENTS: Four asymptomatic HIV-1-infected men. INTERVENTIONS: Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously. MEASUREMENTS AND MAIN RESULTS: Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-infinity) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide. CONCLUSION: Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.
Subject(s)
Anti-HIV Agents/pharmacokinetics , HIV Infections/metabolism , HIV-1 , Semen/metabolism , Zidovudine/pharmacokinetics , Adolescent , Adult , Anti-HIV Agents/blood , Area Under Curve , Glucuronides/blood , Glucuronides/metabolism , HIV Infections/blood , Humans , Male , Zidovudine/bloodABSTRACT
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.
Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/therapeutic use , HIV-1/drug effects , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Therapy, Combination , HIV Infections/metabolism , HIV Protease Inhibitors/blood , HumansABSTRACT
Modification of recombinant human interleukin-2 (IL-2) with polyethylene glycol (PEG-IL-2) decreases clearance and might favor absorption into the lymphatics, due to its increased molecular weight. In the present study, we compared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshire pigs. The IL-2 regimens were i.v. bolus (0.1-1.6 x 10(6) I.U., MIU/kg), 15-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1-3.0 MIU/kg). The PEG-IL-2 doses were 15-min i.v. infusion (0.01 MIU/kg) or s.c. bolus (0.01-0. 10 MIU/kg). Lymph and plasma data were analyzed using noncompartmental methods and NONMEM. Bioavailability of IL-2 was route- and dose-dependent. Bioavailability of i.v. bolus doses of >/=0.16 MIU/kg was complete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavailability was 28 and 42%, respectively. Noncompartmental and NONMEM estimates of clearance and volume of distribution at steady state agreed: 300 ml/h/kg and 570 ml/kg, respectively, for IL-2. The ratio of the area under the curve in lymph and plasma increased from 0.67 to 3.4 when comparing i.v. and s.c. routes, and the s.c. delivery advantage (ratio of dose-normalized ratio of the area under the curve in lymph after s.c. and i.v. administration) was 6.6 to 16. For PEG-IL-2, bioavailability was 100%, clearance was 5.9 ml/h/kg, and volume of distribution at steady state was 370 ml/kg. The ratio of the area under the curve in lymph and plasma increased from 0.33 (i.v.) to 1. 2 (s.c.), and the s.c. delivery advantage was 3.8. Subcutaneous dosing would be favored over i.v. dosing, and IL-2 would be favored over PEG-IL-2 to maximize lymph and minimize plasma exposure. Because IL-2 efficacy may be related to lymph concentrations, dosing regimens can now be designed to test this hypothesis.
Subject(s)
Interleukin-2/pharmacokinetics , Lymph/metabolism , Animals , Area Under Curve , Biological Availability , Body Weight , Excipients , Humans , Injections, Intravenous , Injections, Subcutaneous , Interleukin-2/blood , Interleukin-2/chemistry , Polyethylene Glycols/chemistry , Recombinant Proteins/blood , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Swine , Tissue DistributionABSTRACT
The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m(2) every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of > or =0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m(2); nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean +/- standard deviation) were the following: oral clearance, 1.4 +/- 0.5 liters/h/kg; half-life, 1.1 +/- 0.43 h; and trough concentration, 0. 29 +/- 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Didanosine/pharmacokinetics , Didanosine/therapeutic use , HIV Infections/drug therapy , HIV Infections/metabolism , Indinavir/pharmacokinetics , Indinavir/therapeutic use , Stavudine/pharmacokinetics , Stavudine/therapeutic use , Area Under Curve , Child , Chromatography, High Pressure Liquid , Drug Therapy, Combination , HIV Infections/virology , Half-Life , Humans , Spectrophotometry, Ultraviolet , Time FactorsABSTRACT
BACKGROUND: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.
Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , HIV-1 , Nelfinavir/therapeutic use , Oxazines/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Adolescent , Alkynes , Benzoxazines , CD4 Lymphocyte Count , Child , Child, Preschool , Cyclopropanes , Drug Therapy, Combination , Female , HIV Infections/virology , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/pharmacokinetics , HIV-1/isolation & purification , Humans , Male , Nelfinavir/adverse effects , Nelfinavir/pharmacokinetics , Oxazines/adverse effects , Oxazines/pharmacokinetics , RNA, Viral/blood , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/pharmacokineticsABSTRACT
OBJECTIVES: To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4(+) lymphocyte counts, and plasma HIV RNA concentrations were evaluated. RESULTS: At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4(+) lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy. CONCLUSIONS: Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults.