Therapeutic Dose Range Research Articles

Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma

Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood–brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100–400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3×1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.

Effect of cyclosporin on uropathogenic Escherichia coli adherence to human endothelial cells

The effect of cyclosporin A on the adherence of Escherichia coli strains to human umbilical vein endothelial cells was studied. Compared with the controls, bacterial adherence significantly increased following preincubation of the cells with cyclosporin A at 50 mg/l and more significantly, to cells preincubated with cyclosporin A at 100–200 mg/l. The results showed that cyclosporin A use may be accompanied by an increased bacterial adherence to host cells in vivo. This effect was achieved using a wide range of therapeutic doses.

Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization.

Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effectors. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation. Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the beta-galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided. The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P<.001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51). Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.

Relevance of clinical pharmacological models for the evaluation of therapeutic dose range of an AT1-receptor antagonist

Clinical pharmacological models Antihypertensive drugs affecting the renin-angiotensin system (RAS) can be evaluated in single-dose studies in healthy volunteers challenged with angiotensin I or II, or in subjects in whom the RAS has been activated by salt depletion. Such pharmacological studies can be used to investigate dose-response relationships. Objective The relevance of these models in predicting therapeutic dose range has been evaluated by comparing the results of pharmacological studies with those of a conventional dose-finding study in hypertensive patients with the new AT1-receptor antagonist olmesartan medoxomil. Results In healthy volunteers, 2.5-40 mg olmesartan medoxomil single doses significantly inhibited the pressor response to exogenous angiotensin I. A dose-response relationship was observed, with relevant (> 75%) inhibition occurring at doses of 10 mg and above. In a single-dose crossover study in patients with mild-to-moderate hypertension receiving a sodium-restricted diet, statistically significant lowering of mean 24-h blood pressure, measured by ambulatory blood pressure monitoring, was observed at doses of 10-80 mg. By comparison, a large-scale (n = 792), placebo-controlled, dose-ranging study in patients with mild-to-moderate hypertension likewise showed significant superiority over placebo for 10-80 mg olmesartan medoxomil once-daily doses. Conclusion Single-dose clinical pharmacology studies provided an accurate indication of the effective dose range of a new AT1-receptor antagonist Such models can be useful in identifying, for more detailed study, the likely therapeutic dose range of new drugs acting on the RAS. However, the dose-response still requires testing in large target populations.

The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction.

Orally administered olmesartan medoxomil was rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, the pharmacologically active metabolite that was subsequently excreted without further metabolism. The medoxomil moiety was released as diacetyl that was rapidly cleared by further metabolism and excretion. Peak plasma concentrations of olmesartan occurred 1-3 h after administration, after which concentrations decreased quickly. The elimination half-life was 10-15 h. Olmesartan medoxomil was not measurable in plasma and excreta. The volume of distribution was low, consistent with limited extravascular tissue distribution. Bioavailability (Cmax and area under the curve) increased approximately in proportion with dose, after single and multiple daily oral doses, over the therapeutic dose range (up to 40-80 mg daily), above which systemic availability of olmesartan increased less than proportionally with increase in dose. Steady-state plasma concentrations of olmesartan were reached within the first few daily oral doses. On average, approximately 40% of systemically available olmesartan was excreted by the kidneys, the remainder being excreted in faeces, following secretion in bile. Renal clearance (0.5-0.7 l/h) was independent of dose, accounting for approximately 9-12% of an oral dose. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets was 28.6%. Olmesartan exhibited little or no binding to blood cells. No clinically significant steady-state pharmacokinetic interactions were observed following co-administration of olmesartan medoxomil with digoxin, warfarin and aluminium magnesium hydroxide (antacid), supporting the low potential for clinically significant pharmacokinetic interactions to occur between olmesartan medoxomil and co-administered drugs.

Preclinical Evaluation of CHF3381 as a Novel Antiepileptic Agent

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED 50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED 50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4–5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED 50 ≅ 10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED 50 ≅ 100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED 50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [ 3H]-TCP from binding to NMDA receptor channels ( Ki, 8.8 μM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD 50 ≅ 300 mg/kg p.o., ≅ 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.

Review of rivastigmine and its clinical applications in Alzheimer’s disease and related disorders

Rivastigmine (Exelon™, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer’s disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.

Time Course and Extent of Improvement of Dysfunctioning Myocardium in Patients with Coronary Artery Disease and Severely Depressed Left Ventricular Function after Revascularization: Correlation with Positron Emission Tomographic Findings

Time Course and Extent of Improvement of Dysfunctioning Myocardium in Patients with Coronary Artery Disease and Severely Depressed Left Ventricular Function after Revascularization: Correlation with Positron Emission Tomographic Findings

Synthesis of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives and evaluation of their antidepressant and anxiolytic activity.

Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.

Citalopram Therapy for Depression

This review summarizes and evaluates clinical experience with citalopram, the latest selective serotonin reuptake inhibitor (SSRI) to be approved for the treatment of depression in the United States. Published reports of randomized, double-blind, controlled clinical studies of citalopram were retrieved using a MEDLINE literature search. Search terms included citalopram, SSRI, TCA (tricylic antidepressant), depression, and clinical. For each study, data on antidepressant efficacy and adverse events were evaluated. Pharmacokinetic studies and case reports were reviewed to supplement the evaluation of citalopram's safety and tolerability. Data presented at major medical conferences and published in abstract form also were reviewed. Thirty randomized, double-blind, controlled studies of the antidepressant efficacy of citalopram were located and reviewed. In 11 studies, citalopram was compared with placebo (1 of these studies also included comparison with another SSRI). In 4 additional studies, the efficacy of citalopram in preventing depression relapse or recurrence was investigated. In another 11 studies (including 1 meta-analysis of published and unpublished trials), citalopram was compared with tricyclic and tetracyclic antidepressants. Finally, results are available from 4 studies in which citalopram was compared with other SSRIs. A placebo-controlled study of citalopram for the treatment of panic disorder was reviewed for data on long-term adverse events. Data published over the last decade suggest that citalopram is (1) superior to placebo in the treatment of depression, (2) has efficacy similar to that of the tricyclic and tetracyclic antidepressants and to other SSRIs, and (3) is safe and well tolerated in the therapeutic dose range of 20 to 60 mg/day. Distinct from some other agents in its class, citalopram exhibits linear pharmacokinetics and minimal drug interaction potential. These features make citalopram an attractive agent for the treatment of depression, especially among the elderly and patients with comorbid illness.

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

OBJECTIVESWe sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin.BACKGROUNDLevosimendan is a calcium sensitizer for treatment of acute decompensated heart failure.METHODSA double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 μg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 μg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 μg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a ≥15% increase in stroke volume (SV) at 23 h to 24 h; 2) a ≥25% decrease in pulmonary capillary wedge pressure (PCWP) (and ≥4 mm Hg) at 23 h to 24 h; 3) a ≥40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a ≥50% decrease in PCWP during two consecutive measurements.RESULTSThe response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p ≤ 0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages.CONCLUSIONSDosing of levosimendan with a 10-min bolus of 6 to 24 μg/kg followed by an infusion of 0.05 to 0.2 μg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Vitamin A teratogenicity and risk assessment in the macaque retinoid model

Studies were performed in the cynomolgus monkey ( Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16–27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all- trans-RA, all- trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of ∼25 000 to 37 000 IU/day.

COX-2 selective nonsteroidal anti-Inflammatory drugs: do they really offer any advantages?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for substantial morbidity and mortality as a result of the complications associated with gastroduodenal ulcers, such as perforation and bleeding. The central mechanism leading to the gastroduodenal toxicity of NSAIDs is their ability to inhibit mucosal prostaglandin synthesis. Recent recognition that there are 2 isoforms of the enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis has enabled the development of drugs capable of sparing the gastric mucosa. The inducible COX-2 enzyme is responsible for some aspects of pain and inflammation in arthritis while the constitutive COX-1 enzyme appears responsible for most of the gastro-protective prostaglandin synthesis in the stomach and duodenum. Drugs selective for COX-2 probably act by binding to a pocket in the enzyme that is present in COX-2 but not in COX-1. As a result, drugs that have little or no COX-1 activity across their therapeutic dosage range have been developed. Two drugs that are claimed to be highly selective or specific in their ability to inhibit COX-2, rofecoxib and celecoxib, are now available on prescription in the US and rofecoxib is available in Europe. Short term volunteer studies of 7 days' duration and patient studies of 6 months' duration have shown these drugs to have a level of gastroduodenal injury that is similar or equivalent to that seen with placebo, whereas high rates of damage and ulceration are seen with nonselective NSAIDs. In addition, there appear to have been fewer perforations, clinical ulcers and bleeds in the phase III clinical trials of these agents, compared with nonselective NSAIDS. However, more experience will be needed before this promise can be confirmed. In addition, COX-2 inhibitors share the adverse effects of NSAIDs outside the gastrointestinal tract that are dependent on COX-2 inhibition.

Zaleplon - a review of a novel sedative hypnotic used in the treatment of insomnia

Zaleplon (N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-7-yl) phenyl] -N-ethyl acetamide) is a non-benzodiazepine recently introduced for clinical use. This agent is indicated for the short-term treatment of insomnia. Preclinical studies have shown that the benzodiazepines triazolam and Ro17-1812 can substitute for zaleplon in animals trained to distinguish zaleplon from saline. The benzodiazepine antagonist flumazenil can antagonise the discriminative stimulus effect of zaleplon. These findings suggest that zaleplon is recognised by animals as a benzodiazepine agent. Zaleplon is active after ip. and oral administration in a variety of motor performance tests, including locomotor activity, rotarod and the loaded grid. Zaleplon has been shown to be active in a number of different anticonvulsant models, including the pentylenetetrazole, isoniazid and electroshock models. The compound is also reported to be active against convulsions induced by bicuculline, picrotoxin and strychnine. Studies in anxiolytic models suggest that zaleplon may have weak anxiolytic activity. From preclinical studies, it appears zaleplon possesses a reduced risk of tolerance compared to triazolam, is less likely to potentiate the effects of ethanol and is unlikely to produce amnestic effects. In man, zaleplon is rapidly absorbed and undergoes extensive presystemic metabolism. The compound has a plasma half-life of approximately one hour and is metabolised primarily via the aldehyde oxidase system to form 5-oxo-zaleplon. This metabolite, along with other minor metabolites formed in vivo, do not appear to contribute to the activity of zaleplon. Metabolites of zaleplon are excreted primarily via the urine. Phase I studies suggest that single daytime doses of zaleplon up to 15 mg are well-tolerated. Short-term impairment of performance occurs when zaleplon is administered during the day at doses greater than or equal to 20 mg. However, given the short half-life of the compound, significant impairment of daytime performance is unlikely if zaleplon is administered at bedtime or shortly after retiring for the evening. Results from Phase II/III studies suggest that zaleplon (5 - 20 mg) produces a dose-dependent reduction in sleep latency in patients suffering from primary insomnia. The clinical efficacy of zaleplon persists for at least four weeks at doses of 10 mg and 20 mg. Studies in patients with a history of drug abuse suggest that the abuse potential of zaleplon (at doses above the therapeutic dose range) is similar to that seen with the benzodiazepine triazolam.

522. Efficacy of mirtazapine in stimulant associated insomnia in patients with ADHD

Stimulants are the most commonly prescribed medications for Attention Deficit Hyperactivity Disorder (ADHD). One major side effect of these medications can be an exacerbation or induction of insomnia. ADHD children have been reported as having higher rates of insomnia as compared to psychiatric and pediatric controls; the insomnia was substantially exacerbated by stimulant therapy (Stein MA 1999). Approved hypnotics have not been well studied in stimulant-associated insomnia (SAI). Mirtazapine is a recently marketed antidepressant, which can be mildly sedating in the lower range of therapeutic doses. We now present the findings of an open trial of mirtazapine in ADHD patients with SAI. Sixteen patients with early insomnia and ADHD, who were receiving stimulants, were offered four to six weeks of open clinical treatment with mirtazapine (starting dose: 3.75–7.5 mg qHS, final daily dose: 3.75–45 mg/day, mean: 9.41 ± 10.8 SD mg/day). Two patients developed significant daytime sedation on the first day of treatment and therefore their results are not included. Patients ranged in age from 12 to 47 years of age (mean: 29.8 years). All patients were receiving stable doses of stimulants and met both DSM-IV and childhood K-SADS (self or parent report) criteria for ADHD. Sleep patterns were assessed by self-report of average number of hours slept nightly over the past week, at baseline and then during mirtazapine treatment. Mirtazapine was well tolerated by the remaining fourteen patients. Sleep was improved in all patients (mean hours of sleep: baseline 5.3 ± 1.2; after mirtazapine: 7.9 ± 0.6; t (13) = 11.7, p < 0.0001). All patients elected to continue mirtazapine treatment at the completion of the trial. Mirtazapine significantly improved SAI in this open, pilot trial.

Clinical psychopharmacology of AD/HD: Implications for animal models

A working knowledge of the clinical psychopharmacology of the psychostimulants in AD/HD is essential to the development of valid animal models of the disorder. The clinical pharmacokinetics and pharmacodynamics of d-amphetamine ( d-AMP) and methylphenidate (MPH) have been well-studied. The plasma half-life of these compounds in children is approximately 5 h, with an onset of therapeutic action within a half-hour, and peak action at 1–3 h. The effective dose range for d-AMP in children is 0.2–0.5 mg/kg, and for MPH 0.3–1.0 mg/kg. In humans, psychostimulants bring about reductions in activity level and impulsivity, and improvement in attention span. Enhancement of executive processes mediated in the pre-frontal cortex in humans (especially tolerance for delay) is believed to mediate these therapeutic effects. There are no long-term remedial effects of the drug on behavior—i.e. symptoms return when the drugs are withdrawn. When used in the therapeutic dose range, there is no evidence of the development of significant tolerance or sensitization. These and other clinical findings to be discussed must guide and constrain the development of animal models of stimulant drug effects in AD/HD.

Clinical Pharmacology Studies in Patients with Renal Impairment: Past Experience and Regulatory Perspectives

The objective of this report is to provide a regulatory perspective on the quality of pharmacokinetic studies in renal impairment (RI) studies submitted in support of new drug applications (NBAs) or supplements to NDAs (sNDAs) submitted to the Food and Drug Administration (FDA). Fifty‐one NDA and 20 sNDA submissions reviewed between 1996 and 1997 by the Office of Clinical Pharmacology and Biopharmaceutics were evaluated for the following: (1) whether an RI study was conducted; (2) contribution of the renal clearance to the overall clearance in subjects without renal impairment; (3) degree of plasma protein binding (%PB) in subjects without renal impairment; (4) dose proportionality of single and multiple doses; (5) study design, including dosing regimen; (6) definition of renal impairment; (7) stratification of renal functions; (8) number of subjects/group; (9) data analysis and interpretation; and (10) impact on labeling. Results of the analysis indicated that 67% of the NDAs and 30% of supplemental NDAs contained RI studies (34/51 for NDAs and 6/20 for sNDAs). No obvious differences in the pharmacokinetic characteristics (e.g., percentage excreted unchanged in urine and %PB) were observed between drugs for which RI studies were conducted versus those not conducted. Most studies conducted were designed as single dose (70%). Seventy‐five percent of the studies used doses within the therapeutic dosage range of the drug. The measured 24‐hour creatinine clearance was most often used to assess the renal function. Stratification of renal function ranged from one to five groups, with 6 to 8 subjects enrolled per group. In most studies conducted (38/40), data were analyzed by point estimate using ANOVA. Results of RI studies were adequately reflected in the labeling. The survey reveals that RI study design can be improved for regulatory review purposes. In part based on this analysis, the FDA has prepared a guidance that provides recommendations on the design, analysis, and impact on dosing and labeling for RI studies to include recommendations on when RI studies do not need to be performed. The guidance proposes an equivalence approach with confidence intervals, as opposed to a point estimate approach, to assess the impact of RI on systemic exposure measures.

Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives.

The objective of this report is to provide a regulatory perspective on the quality of pharmacokinetic studies in renal impairment (RI) studies submitted in support of new drug applications (NDAs) or supplements to NDAs (sNDAs) submitted to the Food and Drug Administration (FDA). Fifty-one NDA and 20 sNDA submissions reviewed between 1996 and 1997 by the Office of Clinical Pharmacology and Biopharmaceutics were evaluated for the following: (1) whether an RI study was conducted; (2) contribution of the renal clearance to the overall clearance in subjects without renal impairment; (3) degree of plasma protein binding (%PB) in subjects without renal impairment; (4) dose proportionality of single and multiple doses; (5) study design, including dosing regimen; (6) definition of renal impairment; (7) stratification of renal functions; (8) number of subjects/group; (9) data analysis and interpretation; and (10) impact on labeling. Results of the analysis indicated that 67% of the NDAs and 30% of supplemental NDAs contained RI-studies (34/51 for NDAs and 6/20 for sNDAs). No obvious differences in the pharmacokinetic characteristics (e.g., percentage excreted unchanged in urine and %PB) were observed between drugs for which RI studies were conducted versus those not conducted. Most studies conducted were designed as single dose (70%). Seventy-five percent of the studies used doses within the therapeutic dosage range of the drug. The measured 24-hour creatinine clearance was most often used to assess the renal function. Stratification of renal function ranged from one to five groups, with 6 to 8 subjects enrolled per group. In most studies conducted (38/40), data were analyzed by point estimate using ANOVA. Results of RI studies were adequately reflected in the labeling. The survey reveals that RI study design can be improved for regulatory review purposes. In part based on this analysis, the FDA has prepared a guidance that provides recommendations on the design, analysis, and impact on dosing and labeling for RI studies to include recommendations on when RI studies do not need to be performed. The guidance proposes an equivalence approach with confidence intervals, as opposed to a point estimate approach, to assess the impact of RI on systemic exposure measures.

Inhalation of tobramycin in cystic fibrosis: Part 1: The choice of a nebulizer

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450–1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X 10, X 50, and X 90) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X 50, was within the range of 1–5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300–600 mg have to be nebulized within 20–30 min. It was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC+ (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range.

Memantine does not substantially affect brain stimulation reward: comparison with MK-801

The non-competitive N-methyl- d-aspartate (NMDA)-receptor antagonist MK-801 (dizocilpine) has been shown to potentiate brain stimulation reward (BSR). Memantine (1-amino-3,5-dimethyladamantane) also binds to the PCP binding site of the NMDA receptor but with markedly different kinetics and affinity than MK-801. Here, we examined the effects of memantine on BSR and compared its effects to those of MK-801. MK-801 (0.05 mg/kg–0.4 mg/kg) produced clear, dose-dependent decreases in threshold frequency, manifest in clear leftward shifts of the function relating stimulation frequency to response rate. Memantine (1 mg/kg–17.5 mg/kg) had only small effects on threshold frequencies and only at high doses, manifest in only small shifts in the frequency–response function. The highest dose of each drug also produced a decrease in maximum response rate. This study shows that memantine failed to substantially influence BSR at low to intermediate doses, suggesting that this substance is likely to be largely devoid of rewarding effects in a therapeutic dose range.