A double-blind, placebo-controlled, randomized study to evaluate the weight gain drug, mirtazapine transdermal ointment, in cats with unintended weight loss.

Mirtazapine is classified as a weight gain drug in cats, and the purpose of this study was to evaluate its efficacy in cats experiencing unintended weight loss. This was a multi-center, double-blind, placebo-controlled, randomized clinical study in client-owned cats ≥1 year of age, weighing ≥2 kg, with a documented loss (≥5%) in body weight. Cats were treated once daily with either 2 mg/cat mirtazapine transdermal ointment (n = 83) or placebo (n = 94) (Per Protocol population) applied to the inner surface of the pinna for 14 ± 3 days. Physical examination, body weight, complete blood count, serum chemistry, and urinalysis were performed prior to treatment and on Day 14. Changes in body weight between the mirtazapine and placebo groups were evaluated from Day 1 to Day 14 and compared using a two-sample t test. The mean percent change in body weight was +3.9% (standard deviation ±5.4%) in the mirtazapine group and +0.4% (±3.3%) in the placebo group (p < 0.0001). The most common adverse event was mild erythema at the application site in 17.4% of placebo and 10.4% of mirtazapine-treated cats. Application of mirtazapine transdermal ointment was well tolerated both topically and systemically and resulted in significant weight gain in cats experiencing unintended weight loss associated with various underlying diseases.

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats.

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.

Understanding and evaluating veterinary clinical research.

Results from investigations conducted in clinical settings contribute greatly to determining how veterinarians practice medicine. It is important for the practitioner to understand how clinical information is collected, analyzed, and communicated in journals and presentations at conferences. Clinical research is either retrospective in observational studies, looking at historical medical records as the source of data, or prospective in both experimental and observational studies, where the study is designed before any patients are included. Prospective, experimental studies provide the more reliable results, although they form a minority of published reports. Randomized, controlled trials are the most reliable format, and attempts should be made to use this design more often in veterinary medicine. Care must be taken in the conduct of clinical research to reduce sources of bias that can yield false findings, particularly in small, retrospective studies. Statistical analysis is the key to data interpretation, but must be applied appropriately to avoid either wrong assumptions or misconception. Regardless of how studies are conducted, it is important for the practitioner to be an astute reader of the clinical literature. An understanding of clinical research methods will result in better medical standard of care recommendations and practice.

Compassionate use: a story of ethics and science in the development of a new drug.

This history chronicles the unusual development of the antiviral drug ganciclovir. The first compound with activity against human cytomegalovirus (CMV), ganciclovir was so clearly efficacious that a placebo-controlled clinical trial could not ethically be done, and the FDA rejected the first application to market the drug. Used to treat a blinding eye infection in patients with AIDS, the story of ganciclovir paralleled the spread of the AIDS epidemic. Both ganciclovir and AIDS caught the federal government off guard. Caught in a Catch-22 situation, the pharmaceutical company developing ganciclovir gave the drug away free for five years under compassionate use guidelines. The problems encountered in the development of ganciclovir provide guidance on how future drugs to treat life-threatening diseases can be developed.

A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis.

Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.

High dose oral ganciclovir treatment for cytomegalovirus retinitis.

BACKGROUND: The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. OBJECTIVES: We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. STUDY DESIGN: Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. RESULTS: Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. CONCLUSIONS: This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.