A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation.

BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 µg/mL; γ: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S-IC(50): 0.4, 0.08 µg/mL; γ: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg).

Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients.

BACKGROUND: A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir following oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS: The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS: Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. CONCLUSIONS: The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.

Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients.

BACKGROUND: Valganciclovir (Valcyte) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R-]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R- (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed. METHODS: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene, 1000 mg three times daily) and from valganciclovir (900 mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed. RESULTS: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area under the plasma concentration-time curve values were 46.3 +/- 15.2 microg . h/mL and 28.0 +/- 10.9 microg . h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 +/- 16.1, 40.2 +/- 11.8 and 48.2 +/- 14.6 microg . h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir. CONCLUSION: Oral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.

Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs.

BACKGROUND: Various drug transporters of the ATP-binding cassette (ABC) family restrict the oral bioavailability and cellular, brain, testis, cerebrospinal fluid and fetal penetration of substrate drugs. MDRI P-glycoprotein (P-gp) has been demonstrated to transport most HIV protease inhibitors (HPI) and to reduce their oral bioavailability and lymphocyte, brain, testis and fetal penetration, possibly resulting in major limiting effects on the therapeutic efficacy of these drugs. OBJECTIVES: To investigate whether the ABC transporters MRP1, MRP2, MRP3, MRP5 and breast cancer resistance protein 1 (Bcrp1) are efficient transporters of the HPI saquinavir, ritonavir and indinavir. METHODS: Polarized epithelial non-human (canine) cell lines transduced with human or murine complementary DNA (cDNA) for each of the transporters were used to study transepithelial transport of the HPI. RESULTS: MRP2 efficiently transported saquinavir, ritonavir and indinavir and this transport could be enhanced by probenecid. Sulfinpyrazone was also able to enhance MRP2-mediated saquinavir transport. In contrast, MRP1, MRP3, MRP5, or Bcrp1 did not efficiently transport the HPI tested. CONCLUSIONS: Human MRP2 actively transports several HPI and could, based on its known and assumed tissue distribution, therefore reduce HPI oral bioavailability. It may also limit brain and fetal penetration of these drugs and increase their hepatobiliary, intestinal and renal clearance. MRP2 function and enhancement of its activity could adversely affect the therapeutic efficacy, including the pharmacological sanctuary penetration, of HPI. In vivo inhibition of MRP2 function might, therefore, improve HIV/AIDS therapy.

Oral valganciclovir in children: single dose pharmacokinetics in a six-year-old girl.

We report a pharmacokinetic study in a 6-year-old girl with congenital human immunodeficiency virus type 1 and cytomegalovirus coinfection maintained on iv ganciclovir for 6 years. Increasing infection and thrombosis caused by her iv device necessitated alternative therapy. Single dose pharmacokinetics of ganciclovir 4.4 mg/kg iv and valganciclovir 13.2 and 26.3 mg/kg po were studied with high performance liquid chromatography/tandem mass spectrometry. The two oral dosages yielded areas under the concentration curve of 14.3 and 28.7 microg x h/ml, equivalent to 43% bioavailability of ganciclovir from valganciclovir, which exceeded the area under the concentration curve of 11.1 microg x h/ml yielded by ganciclovir 4.4 mg/kg iv. Oral valganciclovir achieved therapeutic and dosage-proportional plasma concentrations in the child we studied.

Modulation of oral squamous cell carcinoma incidence in rats via diet and a novel calcium channel antagonist.

An unexpected dose related increase in oral squamous cell carcinomas was observed in a standard 2-year carcinogenicity study with a novel calcium channel blocker, in which Wistar rats received daily doses of 0, 1.5, 7, 20, or 40 mg/kg of the compound mixed with a standard diet containing fibers from barley. This finding was associated with an increased incidence of severe (destructive) periodontitis and the formation of oro-nasal fistulae at the 2 highest doses. Five assays of the compound for genotoxicity were negative indicating that a genotoxic effect was highly improbable. To investigate the underlying pathogenic mechanisms a second 2-year study in the same strain of rats was initiated and the influence of the diet and/or a possible local irritancy by the drug was assessed. In this second study the compound was administered by oral gavage at daily doses of 0, 7, or 40 mg/kg (later reduced to 20 mg/kg due to systemic intolerance) to rats maintained either on the standard diet or on a low fiber diet assumed to be less aggressive in terms of inducing periodontal lesions. Dose dependent gingival overgrowth (a class-related effect) was observed in the incisor and molar teeth area of all treated groups but was independent of the diet used. No oral tumors were found in the standard diet or low fiber diet controls and all treatment groups fed the low fiber diet, whereas in the high-dose group fed the standard diet a total of 8 oral squamous cell carcinomas were detected in association with an increased incidence of severe periodontitis. These results indicate that the increased incidence of squamous cell carcinomas observed upon chronic administration of the compound is not due to a direct tumorigenic effect of the drug. Tumor formation is attributable to severe periodontal disease favored by the diet and class related gingival overgrowth.

Factors responsible for the variability of saquinavir absorption: studies using an instrumented dog model.

PURPOSE: To study the effect of dose and food on the bioavailability of saquinavir in dogs. METHODS: A Youden Square block design was used for six female mongrel dogs (20-24 kg) who received six saquinavir treatments. The six randomized treatments were 1 mg/kg intravenous infusion over 30 min; 200, 400, 600, and 800 mg of saquinavir in the form of 200-mg capsules given orally with food; and 400 mg of saquinavir given orally after an overnight fast. A 200-mg 14C-saquinavir capsule was used to replace one of the 200-mg unlabeled saquinavir capsules in the 200- and 800-mg oral study. RESULTS: Absorption of saquinavir from the gut was variable. (F(A): 49-95%). The 14C-saquinavir study shows that the total radioactivity absorbed from the gut was insignificantly different from that of unlabeled saquinavir, suggesting first-pass gut metabolism was unimportant. The bioavailability of saquinavir under fasting condition was significantly lower (8.41 +/- 4.7% vs. 20.3 +/- 2.6%, p < 0.05). Saquinavir underwent significant first-pass liver metabolism because hepatic clearance values (22 to 30 ml min(-1) kg(-1)) approached that of liver blood flow. CONCLUSIONS: Incomplete gut absorption and extensive first-pass liver metabolism are the causes for low bioavailability of saquinavir in dogs. Absorption was further reduced under fasted conditions.

Assessing safety and efficacy of directed P-glycoprotein inhibition to improve the pharmacokinetic properties of saquinavir coadministered with ritonavir.

Using a mouse model, we tested the effects of in vivo P-glycoprotein inhibition to enhance the oral uptake and penetration into pharmacological sanctuary sites of the human immunodeficiency virus protease inhibitor (HPI) saquinavir. The HPI ritonavir is frequently coadministered with saquinavir to improve saquinavir plasma levels since it strongly reduces the cytochrome P450 3A4-mediated metabolism of saquinavir. Previously, we demonstrated that ritonavir is not an efficient P-glycoprotein inhibitor in vivo, evidenced by the limited oral uptake of saquinavir and its penetration into brain and fetus. Increasing drug concentrations in these sites using more effective P-gp inhibitors might improve therapy but could also lead to toxicity. We orally coadministered ritonavir and saquinavir to mice, with or without the potent P-glycoprotein inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). Upon GF120918 coadministration, two of seven P-glycoprotein-deficient animals died. Using a decreased ritonavir dose, GF120918 coadministration led to a 4.4-fold increase in the saquinavir plasma area under the curve in wild-type mice, whereas no such effect was observed in P-glycoprotein-deficient mice. Despite the decreased ritonavir dose, all mice did suffer from impaired gastric emptying. Including GF120918 in a multiple (twice daily) dosing regimen, we found continued accumulation of saquinavir in brain over several days, resulting in 10-fold higher levels compared with vehicle-treated mice. Transient ritonavir-related neurotoxicity, however, was observed after the fourth and final drug dosing. Clinical attempts to efficiently inhibit P-glycoprotein function for improved HPI disposition may therefore be feasible, but they should be performed without ritonavir and monitored carefully for unexpected toxicities.

The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.

Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.