A model-based meta-analysis of the effect of latanoprost chronotherapy on the circadian intraocular pressure of patients with glaucoma or ocular hypertension.

Several reports have demonstrated that the efficacy of latanoprost is influenced by the time of dosing. This model-based meta-analysis validates previous findings that evening dosing is superior to morning dosing and predicts the optimal time for dosing, based on the quantitative assessment of baseline and latanoprost-treated 24-h circadian intraocular pressure (IOP) curves. The results confirm the importance of the time of dosing as a factor that influences the extent of reduction in IOP and underline the need to take this factor into consideration in the design of glaucoma trials and therapy.

Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies.

To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.

National survey of extended-interval aminoglycoside dosing.

A random sample survey of 500 acute care hospitals in the United States was conducted to evaluate the adoption of extended-interval aminoglycoside dosing (EIAD). The survey revealed that EIAD has been adopted in 3 of every 4 acute care hospitals, a 4-fold increase since 1993. Of the 74.7% of hospitals reporting EIAD, 64% had written guidelines. Equal or less toxicity (87.1%), equal efficacy (76.9%), and cost-savings (65.6%) were common rationales. There has been a trend toward higher adult dosages of gentamicin (e.g., >5 mg/kg/dose) and an increase in the adoption of EIAD across all age groups (neonatal, 11%, and pediatric, 23%). Monitoring of aminoglycoside concentrations has shifted to a single determination of concentration, at 6-18 h after drug administration. The most common methods of dosage adjustment for declining renal function were an interval extension with the same dose (47%) or use of the Hartford nomogram (32%).

National survey of once-daily dosing of aminoglycoside antibiotics.

To evaluate the scope of once-daily dosing of intravenous aminoglycoside antibiotics, a questionnaire was designed and mailed to a random sample of pharmacy directors at 500 acute care hospitals in the United States. The response rate was 68.4%. Nineteen percent of the respondents reported use of once-daily dosing of aminoglycosides. Affiliation with a pharmacy residency program and the presence of a pharmacokinetic consultation service by the pharmacy department were associated with this practice (p < 0.05). No other statistically significant differences were found. Reported indications, contraindications, and dosing were consistent with those found in the literature. The profession of pharmacy, as demonstrated by pharmacy residency programs and pharmacokinetic consultation services, appears to have been instrumental in implementing this method of dosing aminoglycosides.

The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer.

BACKGROUND: The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. METHODS: Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine-modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1-hour infusion after a 2-hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high-pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination half-life (T1/2). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. RESULTS: Cyclosporine modulation increased the AUC0-36 of doxorubicin by 48% (P = 0.042) and the AUC0-36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T1/2 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0-36 to the doxorubicin AUC0-36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug-related toxicity was also greater with the cyclosporine-modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubicin (defined by AUC) and the surviving fraction of the leukocyte count (r = -0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporine-modulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = -0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. CONCLUSIONS: The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P-glycoprotein in normal tissues and to selectively inhibit the cytochrome P-450 enzyme system. Further study of this potentially significant drug-drug interaction is warranted.