First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

AIMS: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P1 -desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization). METHODS: SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed. RESULTS: SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings. CONCLUSION: SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.

Machine learning and molecular descriptors enable rational solvent selection in asymmetric catalysis.

Rational solvent selection remains a significant challenge in process development. Here we describe a hybrid mechanistic-machine learning approach, geared towards automated process development workflow. A library of 459 solvents was used, for which 12 conventional molecular descriptors, two reaction-specific descriptors, and additional descriptors based on screening charge density, were calculated. Gaussian process surrogate models were trained on experimental data from a Rh(CO)2(acac)/Josiphos catalysed asymmetric hydrogenation of a chiral α-ß unsaturated γ-lactam. With two simultaneous objectives - high conversion and high diastereomeric excess - the multi-objective algorithm, trained on the initial dataset of 25 solvents, has identified solvents leading to better reaction outcomes. In addition to being a powerful design of experiments (DoE) methodology, the resulting Gaussian process surrogate model for conversion is, in statistical terms, predictive, with a cross-validation correlation coefficient of 0.84. After identifying promising solvents, the composition of solvent mixtures and optimal reaction temperature were found using a black-box Bayesian optimisation. We then demonstrated the application of a new genetic programming approach to select an appropriate machine learning model for a specific physical system, which should allow the transition of the overall process development workflow into the future robotic laboratories.

Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.

Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations.

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single-dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple-dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration-time profile over the interval of last quantifiable point to infinity (AUC(0-infinity)) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32-1.86) in the single-dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04-1.39) for day 14 area under the concentration-time profile calculated over the interval 0 to 24 hours (AUC(0-24h)) following multidose. The AUC(0-infinity) GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51-2.06) following 70 mg; AUC(0-24h) GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90-1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate hepatic insufficiency.

Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women.

Human immunodeficiency virus-infected women (n=16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.

Pharmacokinetics of ertapenem in patients with varying degrees of renal insufficiency and in patients on hemodialysis.

Ertapenem is a parenteral beta-lactam carbapenem antibiotic. This open-label study examined the pharmacokinetics of single 1-g intravenous doses of ertapenem, administered over 30 minutes, in patients with mild, moderate, and advanced renal insufficiency (RI) and in patients with end-stage renal disease (ESRD) requiring hemodialysis. Pharmacokinetics were compared with historical controls pooled across healthy young and elderly subjects. Area under the concentration-time curve from time zero to infinity increased 7% in mild, 53% in moderate, 158% in advanced RI, and 192% in ESRD; end of infusion concentration changed minimally; half-life was 4.5 hours in the historical control group and 4.4, 6.1, 10.6, and 14.1 hours in mild RI, moderate RI, advanced RI, and ESRD, respectively. Hemodialysis cleared approximately 30% of the dose. The recommended dose in mild to moderate RI and after hemodialysis is unchanged at 1 g daily; and in advanced RI and ESRD is reduced to 0.5 g daily. If the daily dose is given 6 hours prior to hemodialysis, a supplementary 150-mg dose (30% of the daily dose) is recommended postdialysis.

Vocational outcomes after brain injury in a patient population evaluated for Life Care Plan reliability.

This retrospective cohort study examined the vocational outcomes in forty-four traumatically brain injured patients. Patient files selected were limited to those who were seen for the development of an original Life Care Plan and were subsequently seen at least once for a complete update of that plan. Patients who were retired at the time of the brain injury were excluded. Each participant was actively involved in litigation at the time of the initial evaluation as well as at the time of his or her update evaluation. Traumatic brain injury resulted from various etiologies. Vocational outcomes were analyzed in relation to severity of injury, age at onset, gender and education. Vocational outcome was reported as a return to work, supported employment, return to school or training or permanent total disability. Twenty-one patients were classified as permanent-total disabilities. Twenty-three returned to work, supported employment, or were successfully in school and expected to return to work. This 52% rate of vocational or school participation is particularly noteworthy since all cases were actively in litigation. A significant trend was found for severity of injury, and level of education, but not for age at onset or gender. These factors are discussed in relation to the subjects' participation in third party civil litigation and implications for Life Care Planning.

Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.

Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.

A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients.

Breast cancer comprises a group of distinct subtypes that despite having similar histologic appearances, have very different metastatic potentials. Being able to identify the biological driving force, even for a subset of patients, is crucially important given the large population of women diagnosed with breast cancer. Here, we show that within a subset of patients characterized by relatively high estrogen receptor expression for their age, the occurrence of metastases is strongly predicted by a homogeneous gene expression pattern almost entirely consisting of cell cycle genes (5-year odds ratio of metastasis, 24.0; 95% confidence interval, 6.0-95.5). Overexpression of this set of genes is clearly associated with an extremely poor outcome, with the 10-year metastasis-free probability being only 24% for the poor group, compared with 85% for the good group. In contrast, this gene expression pattern is much less correlated with the outcome in other patient subpopulations. The methods described here also illustrate the value of combining clinical variables, biological insight, and machine-learning to dissect biological complexity. Our work presented here may contribute a crucial step towards rational design of personalized treatment.

Potential for interactions between caspofungin and nelfinavir or rifampin.

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24h) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24h) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.

Pharmacokinetics of montelukast in asthmatic patients 6 to 24 months old.

Montelukast is a cysteinyl leukotriene receptor antagonist approved for the treatment of asthma for those ages 1 year old to adult. The purpose of this study was to evaluate the pharmacokinetic comparability of a 4-mg dose of montelukast oral granules in patients > or = 6 to < 24 months old to the 10-mg approved dose in adults. This was an open-label study in 32 patients. Population pharmacokinetic parameters included estimates of AUC(pop), C(max), and t(max). Results were compared with estimates from adults (10-mg film-coated tablet [FCT]). Dose selection criteria were for the 95% confidence interval (CI) for the AUC(pop) estimate ratio (pediatric/adult 10 mg FCT) to be within comparability bounds of (0.5, 2.00). The AUC(pop) ratio and the 95% CI for children compared with adults were within the predefined comparability bounds. Observed plasma concentrations were also similar. Based on systemic exposure of montelukast, a 4-mg dose of montelukast appears appropriate for children as young as 6 months of age.

Indinavir and rifabutin drug interactions in healthy volunteers.

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma.

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 microCi) of [(3)H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [(3)H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t(1/2) = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at approximately 92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.

Pharmacokinetics of intramuscularly administered ertapenem.

Ertapenem (INVANZ) is a new once-a-day parental beta-lactam antimicrobial agent that has been shown to be highly effective as a single agent for treatment of various community-acquired and mixed infections. The plasma pharmacokinetics of a 1-g intramuscular (i.m.) dose was compared with those of a 1-g intravenous (i.v.) dose infused over 30 min, the recommended rate of i.v. infusion for comparison, and over 120 min, which more closely mimicked the time course for absorption of the i.m. form. In a three-period crossover study (Part A), 26 healthy subjects received single doses of ertapenem administered i.m., i.v. infused over 30 min, and i.v. infused over 120 min. Blood for ertapenem analysis was collected over 24 h postdose for each treatment. In Part B, these fasted subjects received a 1-g i.m. dose of ertapenem once daily for 7 days. Following a 1-g i.m. dose and a 1-g i.v. dose infused over 120 min, the geometric mean area under the concentration curve from hour 0 to infinity (AUC(0- infinity )) was 541.8 micro g. hr/ml following i.m. administration and 591.4 micro g. hr/ml following a 120-min infusion; the geometric mean ratio was 0.92 with a 90% confidence interval of 0.88 to 0.95. The geometric mean AUC(0- infinity ) was nearly identical when 1-g doses were infused over 30 or 120 min. Although the maximum concentration of drug in serum was somewhat lower following i.m. administration than following i.v. administration, the shape of the plasma concentration profiles was roughly comparable at later time points. Ertapenem did not accumulate after multiple 1-g i.m. daily doses over 7 days. The geometric mean ratio for AUC(0-24) (day 7/day 1) was 0.98 with a 90% confidence interval of 0.94 to 1.02. Thus, the relative bioavailability of the 1-g i.m. dose was 92%. Ertapenem does not accumulate following multiple daily 1-g i.m. doses over 7 days.

Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.

BACKGROUND: Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours. CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.

Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.

Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics, and antiretroviral activity.

Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4(+) cell count of 266 cells/mm(3). Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).