En Bloc Multivisceral and Kidney Transplantation in an HIV Patient: First Case Report.

The continual improvement in outcome with highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection and visceral transplantation for gut failure stimulated our interest in lifting HIV infection as a contraindication for intestinal and multivisceral transplantation. This report is the first to describe visceral transplantation in a patient with HIV infection. A HAART regimen was introduced in the setting of short-gut syndrome with successful suppression of HIV viral load. The indication for en bloc multivisceral and kidney transplantation was end-stage liver failure with portomesenteric venous thrombosis and chronic renal insufficiency. The underlying hepatic pathology was alcoholic and home parenteral nutrition-associated cirrhosis. Surgery was complicated due to technical difficulties with excessive blood loss and long operative time. The complex posttransplant course included multiple exploratory laparotomies due to serious intra-abdominal and systemic infections. Heavy immunosuppression was required to treat recurrent episodes of severe allograft rejection. Posttransplant oral HAART successfully sustained undetectable viral load. Unfortunately, the patient succumbed to sepsis 3 months posttransplant. With new insights into the biology of gut immunity, mechanisms of allograft tolerance, and HIV-associated immune dysregulation, successful outcome is anticipated, particularly in patients who are in need of isolated intestinal and less-organ-contained visceral allografts.

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV-infected Ugandans.

BACKGROUND: Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. METHODS: Efavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenz- based regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. RESULTS: The mean steady-state minimum plasma concentration (C(min) ) of efavirenz was 2.9 µg/mL, the mean area under the curve (AUC) was 278.5 h µg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C(max) ) of efavirenz was >4 µg/mL in 96.6% of participants, while C(min) was <1 µg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations >4 µg/mL, although only half maintained a high concentration until at least 8 h after dosing. CONCLUSION: The findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C(max) , regardless of the sampling time.

Plasma efavirenz concentration inversely correlates with increased risk of cytomegalovirus infection in HIV-infected pregnant women.

BACKGROUND: Effective combination antiretroviral therapy (cART) has tremendously reduced HIV-associated morbidity, mortality and mother-to-child transmission. However, the benefits of cART are threatened by comorbidities, adverse drug reactions and virus resistance to existing treatment regimens. One of the most occurring comorbidities is cytomegalovirus (CMV) infection. OBJECTIVES: To investigate the effects of cART on the occurrence of CMV infection among pregnant women. METHODS: Using a cross-sectional study design, 175 HIV-infected pregnant women were recruited, and data were obtained from their clinical records. Blood samples were collected for host DNA, CMV DNA and plasma efavirenz (EFV) measurement. CMV DNA was measured using real-time polymerase chain reaction (PCR). CYP2B6 c.516G>T and CYP2B6 c.983T>C single nucleotide polymorphisms were characterised using PCR/restriction fragment length polymorphism and TaqMan assays, respectively. Plasma EFV concentrations were determined using high-performance liquid chromatography. RESULTS: There was an inverse association between plasma EFV concentration and CMV DNA. Participants with lower plasma EFV concentrations were significantly (p<0.001) more likely to be CMV DNA positive than those with higher plasma concentrations. This result is also supported by the observation that carriers of CYP2B6 poor-metaboliser genotypes (CYP2B6 c.516T/T and CYP2B6 c.983T/C) were less likely to be positive for CMV DNA. Furthermore, poor metabolism as denoted by CYP2B6 c.516T/T and CYP2B6 c.983T/C genotypes was significantly associated with lower CMV viral load. CONCLUSIONS: HIV treatment disrupts the balance between host and co-infecting microbes. Reduced or subtherapeutic levels of antiretroviral drugs, which could be exacerbated by genetic polymorphisms in drug metabolism genes and non-adherence, predispose infected individuals to an increased risk of CMV infection in pregnancy.

Positive reinforcement targeting abstinence in substance misuse (PRAISe): Study protocol for a Cluster RCT & process evaluation of contingency management.

There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals. With an international evidence base for CM, NICE recommended that CM be implemented in UK drug treatment settings alongside OST to target attendance and the reduction of illicit drug use. While there was a growing evidence base for CM, there had been no examination of its delivery in UK NHS addiction services. The PRAISe trial evaluates the feasibility, acceptability, clinical and cost effectiveness of CM in UK addiction services. It is a cluster randomised controlled effectiveness trial of CM (praise and financial incentives) targeted at either abstinence from opiates or attendance at treatment sessions versus no CM among individuals receiving OST. The trial includes an economic evaluation which explores the relative costs and cost effectiveness of the two CM intervention strategies compared to TAU and an embedded process evaluation to identify contextual factors and causal mechanisms associated with variations in outcome. This study will inform UK drug treatment policy and practice. Trial registration ISRCTN 01591254.

Update on the pharmacokinetic aspects of antiretroviral agents: implications in therapeutic drug monitoring.

The observed inter-individual variation in antiretroviral pharmacokinetics (PK) that results in a wide range of drug exposures from fixed-dose regimens has led to increasing interest in the clinical use of therapeutic drug monitoring (TDM) to individualize dosing of antiretroviral therapy (ART). The focus of this review is to provide an overview of literature available to support therapeutic drug monitoring among the current classes of antiretrovirals, suggest patient populations that may benefit from TDM and bring forth some of the limitations that may exist for widespread use of TDM in a traditional clinical setting.

Pharmacokinetics and clinical tolerance of intravenous and oral cyclosporine in the immediate postoperative period.

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 +/- 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 +/- 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 +/- 0.1 L/min and a volume of distribution of 2.88 +/- 1.1 L/kg, whereas the elimination half-life was 12.8 +/- 3.8 hours and the mean residence time was 9.5 +/- 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 +/- 0.13 and 0.30 +/- 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.

Moxalactam epimer disposition in patients undergoing continuous ambulatory peritoneal dialysis.

The kinetics of the epimers of moxalactam (R-MOX, S-MOX) were investigated in patients without infections who were receiving continuous ambulatory peritoneal dialysis after both intravenous and intraperitoneal injections of moxalactam. R-MOX and S-MOX were well absorbed from the peritoneal cavity, with mean systemic availability of 0.71 +/- 0.18 and 0.79 +/- 0.18, respectively. After intravenous MOX, serum clearance was 10.2 +/- 3.4 (R-MOX) and 10.9 +/- 3.2 (S-MOX) ml/hr/kg. Net time-averaged peritoneal dialysis clearance of both epimers was minimal, about 10% of serum clearance. Serum and dialysate MOX concentrations were above the minimum inhibitory concentrations for susceptible bacteria for 24 hours after a 2.0 or 1.0 gm intravenous or intraperitoneal dose. Gastrointestinal side effects occurred after a 2.0 gm dose (both intravenous and intraperitoneal) but not after a 1.0 gm dose. There were no significant differences in the kinetics of R-MOX and S-MOX. A single 1.0 gm ip dose leads to serum and dialysate MOX concentrations above the minimum inhibitory concentration for susceptible pathogens for 24 hours.

Pharmacokinetic modeling of bidirectional transfer during peritoneal dialysis.

A pharmacokinetic model and distributional clearance terms to describe bidirectional peritoneal transfer were used to examine cefamandole pharmacokinetics in five uninfected patients with end-stage renal disease who were receiving continuous ambulatory peritoneal dialysis. Each patient received intravenous and intraperitoneal 1 gm doses of drug, and serum and dialysate samples were collected over three dialysis dwell periods. The mean systemic availability of cefamandole after intraperitoneal dosing was 0.71 +/- 0.1. No significant differences in the serum-to-peritoneal fluid and peritoneal fluid-to-serum distributional clearances were observed. The time dependence of peritoneal dialysis clearance was examined. The amount of drug found in the dialysate divided by the corresponding serum AUC was empirically found to estimate the time-averaged peritoneal dialysis clearance. A mass balance-area method to calculate distributional clearance was developed that obviates more complicated computer fitting of the data. We present a comprehensive modeling approach that should be useful in the examination of the kinetics of drugs during continuous ambulatory peritoneal dialysis.

Cost-effectiveness evaluation of three approaches to case management for homeless mentally ill clients.

OBJECTIVE: In this study the authors compared the cost-effectiveness of three approaches to case management for individuals with severe mental illness who were at risk for homelessness: assertive community treatment alone, assertive community treatment with community workers, and brokered case management (purchase of services). METHOD: Individuals were randomly assigned to the three treatment conditions and followed for 18 months. Eligibility requirements included a severe DSM-III axis I diagnosis, such as schizophrenia, and either current homelessness or risk for homelessness based on prior history of homelessness. Participants were recruited from the emergency rooms and inpatient units of local psychiatric hospitals. Data on 85 people were available for analyses: 28 in assertive community treatment alone, 35 in assertive community treatment with community workers, and 22 receiving brokered case management (purchase of services). RESULTS: Clients assigned to the two assertive community treatment conditions had more contact with their treatment programs, experienced greater reductions in psychiatric symptoms, and were more satisfied with their treatment than clients in the brokered condition. There was no statistically significant difference between treatment conditions in terms of the total costs of treating the participants. However, the assertive community treatment conditions spent less money on inpatient services than brokered case management, but more on case management services and maintenance (i.e., food stamps, housing subsidies, and Supplemental Security Income payments). CONCLUSIONS: Assertive community treatment has better client outcomes at no greater cost and is, therefore, more cost-effective than brokered case management.

Methylprednisolone disposition in renal transplant recipients receiving triple-drug immunosuppression.

Renal transplant patients commonly receive triple-drug immunosuppression with standardized doses of cyclosporine, azathioprine, and methylprednisolone. Although cyclosporine may decrease the clearance of oral prednisone, data are lacking for methylprednisolone, a glucocorticoid commonly prescribed via a standardized protocol for intravenous therapy and during periods of acute rejection. The disposition of methylprednisolone (doses: 10-60 mg/day) was examined in nine renal transplant patients during the post-transplant period (0.8-14 months). Plasma samples were collected over 24 hr and analyzed for methylprednisolone via HPLC. Pharmacokinetic parameters were determined by noncompartmental analysis. The mean total clearance of methylprednisolone was 379 ml/hr/kg (range 105-672) and the volume of distribution was 1.4 +/- 0.5 L/kg. The mean plasma half-life was 2.7 +/- 1.1 hr. When normalized to a 1 mg dose of methylprednisolone, the mean peak concentration at 1 hr was 10.0 +/- 3.5 ng/ml with an 8 hr concentration ranging from 0.3 to 5.5 ng/ml. An appreciable variability in methylprednisolone metabolism thus exists in renal transplant recipients receiving triple-drug immunosuppression. This may partially explain the variable response to steroid therapy during acute rejection episodes and chronic immunosuppression as well as the unpredictable occurrence of chronic steroid toxicity.

Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Comparative pharmacokinetics of antiviral nucleoside analogues.

The recent development of nucleoside analogues with antiviral activity has expanded the small but useful armamentarium for the treatment of certain viral diseases such as the human immunodeficiency virus, cytomegalovirus and others. Their intracellular site of action and need for sequential phosphorylation require that traditional pharmacokinetic parameters be used in conjunction with an understanding of intracellular metabolism when designing dosage regimens. This review summarises the available pharmacokinetic literature for zidovudine, didanosine, zalcitabine, aciclovir, ganciclovir, vidarabine and ribavirin. After oral administration, didanosine, aciclovir and ribavirin are < 50% bioavailable and ganciclovir is < 6% absorbed. In contrast, zidovudine and zalcitabine are > 60% bioavailable, although zidovudine undergoes considerable and variable first-pass hepatic glucuronidation while zalcitabine has no first-pass effect. Zidovudine, zalcitabine and didanosine are absorbed rapidly in the fasted state, with peak plasma concentrations exceeding their respective in vitro antiretroviral inhibitory concentrations. All reviewed agents except ribavirin have a relatively short plasma half-life (approximately 0.5 to 4h), with each agent demonstrating a different intracellular enzymatic activation scheme. For example, the rate-limiting step for formation of zidovudine triphosphate is the conversion of the monophosphate to the diphosphate, while didanosine is ultimately converted to dideoxyadenosine triphosphate which has the longest intracellular half-life (approximately 12 to 24h) among these agents. These drugs are not highly protein bound and they distribute into tissues with an apparent volume of distribution at steady-state ranging from 0.3 to 1.2 L/kg. They vary in the extent to which they enter cerebrospinal fluid, ranging from a low of < 25% for didanosine to a high of > 70% of a concurrent plasma concentration for ribavirin and vidarabine. These agents also vary with regard to degree of renal excretion of the parent drug, with the lowest noted for vidarabine (1 to 3%) and the highest for zalcitabine (approximately 75%) and ganciclovir (> 90%). With the increasing number of clinically useful nucleoside analogues, it is essential for the clinician to appreciate the subtle differences among these agents to ensure that optimal therapeutic outcomes may be attained with minimal toxicity.

Intravascular distribution of zidovudine: role of plasma proteins and whole blood components.

Knowledge of drug protein-binding and blood cell partitioning may be important for evaluating the pharmacokinetic parameters of zidovudine, particularly because of its intracellular site of action and potential to induce side effects. Equilibrium dialysis studies of zidovudine were performed over 2 h to identify the extent and site of binding. Zidovudine was added to anticoagulated whole blood to study blood cell distribution over a 24 h period at 37 degrees C and at 21 degrees C. Concurrent plasma and whole blood samples were determined at various time-points and blood partitioning was determined by application of a mass balance equation. All samples were analyzed using radioimmunoassay. The free fraction of zidovudine at a concentration of 500 ng/ml (1.7 microM) was 0.77 +/- 0.05 in plasma, 0.78 +/- 0.03 in serum, 0.88 +/- 0.03 in 4 g/dl albumin solution, and 1.0 in 100 mg/dl alpha 1-acid glycoprotein solution. A free fraction of 0.72 +/- 0.10 was observed in plasma from HIV-infected patients with zidovudine concentrations ranging from 16 to 91 ng/ml. Zidovudine equilibration between plasma and blood cells occurred rapidly, being complete within 10 min. After equilibrium was complete, the mean whole blood:plasma ratio was 0.86 +/- 0.02 and 0.80 +/- 0.04 (P = 0.20) and mean blood cell Partitioning ratio, [cell]/[plasma-free], was 0.85 +/- 0.06 and 0.66 +/- 0.14 (P = 0.25) for studies at 37 degrees C and 21 degrees C, respectively. The partitioning ratio was relatively consistent over the study period, suggesting no accumulation in blood cells. These results suggest that zidovudine binds to a small extent primarily to albumin. The free concentration equilibrates readily between blood cells and plasma independent of concentration and without signs of accumulation.

In vitro protein-binding characteristics of delavirdine and its N-dealkylated metabolite.

This study was performed to determine delavirdine protein-binding characteristics as well as those of its N-dealkylated metabolite (N-DLV). Initial studies of 36 microM delavirdine and 30 microM N-DLV in solutions of plasma, albumin 4 g%, alpha-1-acid glycoprotein (AAG) 100 mg% or immune globulin (IVIG) 5 g% were conducted. Delavirdine (12, 36 and 73 microM) and N-DLV (10, 30 and 60 microM) were then studied alone and in combination in plasma and various concentrations of albumin. Studies were done in triplicate using equilibrium dialysis. The mean delavirdine fraction unbound (fu) in plasma, albumin, IVIG and AAG was 0.013, 0.033, 0.752 and 0.912 while the mean fu of N-DLV in these same protein solutions was 0.139, 0.195, 0.329 and 0.359. In plasma and albumin, a greater fu was observed at higher delavirdine concentrations and no significant changes in fu were noted with the addition of N-DLV. An increase in delavirdine fu was noted as the albumin concentrations decreased. The fu of N-DLV increased significantly as the concentration of albumin decreased as well as with decreasing N-DLV concentration. The potential implications of extensive delavirdine binding to plasma proteins, primarily albumin, are discussed.

Pharmacokinetics of orally administered zidovudine among patients with hemophilia and asymptomatic human immunodeficiency virus (HIV) infection.

Zidovudine (formerly azidothymidine, AZT) is used to treat certain patients infected with the human immunodeficiency virus (HIV). However, the clinical use of zidovudine (ZDV) in hemophilia patients may be complicated by the high incidence of chronic hepatitis in this patient population. To examine the pharmacokinetics of ZDV eight asymptomatic HIV-infected hemophilia patients received a single oral dose (300 mg). ZDV and its glucuronide metabolite (GZDV) were measured in serum by HPLC. ZDV was rapidly absorbed with a wide range of peak serum concentrations (2052 +/- 970 ng/ml) at 0.5 h. Peak GZDV serum concentrations were 4751 +/- 2269 ng/ml at 1 h. Both ZDV and GZDV declined in a biexponential manner over 4 h. After 4 h, the ZDV serum concentration decay in three patients continued a log-linear decline, while five patients demonstrated a tri-exponential curve which had a mean terminal elimination half-life of 4.8 +/- 2.8 h. No relationship between ZDV or GZDV kinetics and the degree of hepatic enzyme elevation was observed. Although a therapeutic window for ZDV has yet to be described, the wide range of serum concentrations that result from a standard dose suggests that clinical monitoring of ZDV levels may be of value in certain patients. In addition, the prolonged elimination half-life of ZDV in the present study may provide a rationale for less frequent dosing in certain patients.

In vitro protein-binding characteristics of atevirdine and its N-dealkylated metabolite.

The in vitro protein-binding characteristics of atevirdine (ATV), a non-nucleoside reverse transcriptase inhibitor with activity against HIV-1, and its N-dealkylated metabolite (N-ATV) were studied using equilibrium dialysis. ATV and N-ATV were studied at concentrations of 5, 10, 20, and 30 microM in five protein-containing solutions [albumin 4%, plasma, serum, immune globulin (IgG) 1.5%, alpha 1-acid glycoprotein (AAG)] for 5 h at 37 degrees C. All samples were analyzed by high-performance liquid chromatography. The free fraction of atevirdine in plasma, albumin, and serum was 0.01-0.02 over the range of drug concentrations studied. The fraction unbound (fu) in these protein solutions statistically differed from IgG and AAG (P < 0.05), where the fraction unbound averaged 0.96 and 0.53, respectively. N-ATV had a similar binding profile as ATV with a fraction unbound of 0.04, 0.03, 0.03 in albumin, plasma and serum, respectively. A difference existed in N-ATV binding when compared to IgG and AAG with an average fu of 0.87 and 0.59 (P < 0.05 vs. plasma). The potential clinical implications of the high degree of protein binding for ATV and N-ATV are discussed.

Pharmacokinetics of zidovudine and didanosine during combination therapy.

While the combination of zidovudine and didanosine is used in HIV-infected patients with more advanced disease, the possibility of a pharmacokinetic interaction between these two drugs remains controversial. Zidovudine doses of 50, 100, and 200 mg, combined with 67, 167, and 250 mg of didanosine were evaluated in 11 asymptomatic HIV-infected patients after receiving 24 weeks of combination therapy in AIDS Clinical Trials Group protocol 143. The pharmacokinetic parameters of zidovudine and didanosine were similar to those obtained with each drug given as monotherapy in other previously published studies. The renal clearance and urinary recovery of glucuronidated zidovudine was reduced when zidovudine was given in combination with didanosine, possibly due to competition for renal tubular secretion. These data suggest that no clinically important pharmacokinetic interaction occurs when zidovudine and didanosine are given together.

Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199 study teams.

RATIONALE: To determine the dosage requirements and pharmacokinetics of atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkylated metabolite (N-ATV) during phase I studies in patients receiving atevirdine alone or in combination with zidovudine. DESIGN: Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which atevirdine was administered every 8 h with weekly dosage adjustments to attain targeted trough plasma atevirdine concentrations. SETTING: Five Adult AIDS Clinical Trials Units. PATIENTS: Fifty patients (ACTG 199; n = 20 and ACTG 187; n = 30) with HIV-1 infection and < or =500 CD4+ lymphocytes/mm3. INTERVENTION: ACTG 199; 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5-10 microM) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31 microM). MEASUREMENTS: ACTG 199: atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) prior to and at 6 and 12 weeks during combination therapy. ACTG 187: atevirdine and N-ATV trough concentrations over a 12 week period. Intensive pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during atevirdine monotherapy in female patients. RESULTS: Atevirdine plasma concentrations demonstrated considerable interpatient variability which was minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to achieve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained the target, was group I (5-11 microM): 2.7+/-2.4 weeks (92%); group II (12-21 microM): 2.6+/-1.8 (64%); and group III (22-31 microM): 7.0+/-5.6 weeks (27%). In ACTG 199 it was 3.2+/-5.2 weeks (95%) to achieve a 5-10 microM trough. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absorption with Cmax at 0.5-1 h, delayed absorption with Cmax at 3-4 h; minimal Cmax to Cmin fluctuation and Cmax to Cmin ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized on day one by rapid appearance of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. At steady-state N-ATV patterns demonstrated minimal Cmax to Cmin fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. CONCLUSIONS: Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition was reflected in the range of daily doses required to attain the targeted trough concentrations. Atevirdine metabolism did not appear to reach saturation during chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV ratios in plasma and saturation was not an explanation for the variation in dosing requirements. No apparent differences were noted between males and females, and atevirdine did not appear to influence zidovudine disposition.

Disposition of intramuscular cefonicid in elderly patients.

OBJECTIVE: To examine the disposition of intramuscular (IM) cefonicid in elderly patients with bacterial pneumonia. DESIGN: Pharmacokinetic study. SETTING: A 620-bed university-affiliated long-term care institution with its own 39-bed acute care unit. PATIENTS: Nine consecutive elderly patients with bacterial pneumonia treated with IM cefonicid. MEASUREMENTS: Blood samples were collected on the seventh day of therapy over a 24-hour period and analyzed by high performance liquid chromatography. Pharmacokinetics parameters (volume of distribution, half-life, and clearance) and protein binding were calculated. Clinical outcome of IM cefonicid therapy was also noted. RESULTS: The estimated creatinine clearance (CIcr) ranged from 32 to 145 mL/min. Peak cefonicid serum concentrations occurred at 0.5-1.5 hours, with a mean value of 118 +/- 41 micrograms/mL. Cefonicid concentrations declined monoexponentially to 57 +/- 16 micrograms/mL at 12 hours and 28 +/- 14 micrograms/mL at 24 hours. The mean apparent distribution volume was 0.2 +/- 0.07 L/kg, and the mean apparent total clearance was 15 +/- 12 mL/min. The half-life ranged from 3.1 to 38 hours. A linear correlation was noted between Clcr and cefonicid clearance (r = 0.99). CONCLUSIONS: Cefonicid absorption was variable among these patients, and the serum half-life was longer than previous values noted in younger patients with similar degree of renal dysfunction. Pharmacokinetic and clinical outcome data from our study group indicate the potential role of IM cefonicid in treating elderly patients with bacterial pneumonia.

Granulocyte-macrophage colony-stimulating factor and zidovudine in the treatment of neutropenia and human immunodeficiency virus infection.

Granulocyte-macrophage colony-stimulating factor (GMCSF) is a hematopoietic protein that has been studied both in vitro and in vivo in human immunodeficiency virus (HIV) infection. Since both HIV infection primarily and zidovudine (formerly AZT) treatment secondarily may result in neutropenia, administration of GMCSF to persons with HIV infection is generating considerable interest. Despite in vitro studies demonstrating that the agent may stimulate HIV replication, in the presence of zidovudine a synergistic inhibition of replication occurs. Early clinical studies in patients with the acquired immunodeficiency syndrome indicate that GMCSF can raise neutrophil counts with or without concurrent zidovudine treatment. The long-term safety and tolerance of the combination has to be established.