Once-per-day dosing

The goal of most drug discovery programs is to develop a drug in a formulation that allows for once-per-day dosing. Daily dosing is sufficiently frequent so that patients do not forget to take their medication while not so frequent to be an inconvenience. 

When the early work on the amino-containing compounds showed that they had significant spectrum improvements and intrinsic water solubility, additional analogues were screened for a variety of biological and chemical properties, and especially for once per day dosing. MK-0911 (L-743,872, the heminaminal aza analogue of L-733,560, (Fig. 2) was found to have pharmacokinetic and safety advantages over other derivatives and was therefore selected as the clinical candidate. 

Trial objectives may also incorporate commercial imperatives. The marketing department may suggest that the treatment regimen must be once per day to be successful in the market. This requirement affects optimal dose... 

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

Pegfilgrastim Neulasta Neutrophil 6 mg SQ one time Bone pain (approximately 25%) Once per cycle dosing Administer 1-3 days after chemotherapy... 

Naltrexone is prescribed at a dose of 50 mg once per day for at least 12 weeks as part of a comprehensive alcohol treatment program. Like all treatments for substance use disorders, it works only as well as the addict allows it to work. This is why it is important to use it as a component of an overall treatment plan. Otherwise, poorly motivated alcohol abusers will seldom remain adherent with naltrexone and it will have little chance of providing benefit. A long-acting depot formulation of naltrexone currently in development might improve these compliance problems. 

Initial dosage The recommended starting dosage is 25 mg given 3 times/day at the start (with the first bite) of each main meal. However, some patients may benefit from more gradual dose titration to minimize Gl side effects. This may be achieved by initiating treatment at 25 mg once per day and subsequently increasing the frequency of administration to achieve 25 mg three times daily. 

Children 6 years of age and older- 0.2 mg/kg once per day as monotherapy. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients. 

SILDENAFIL 50 mg taken as needed approximately 1 hour before sexual activity. However, sildenafil may be taken anywhere from 4 hours to 30 minutes before sexual activity. Based on effectiveness and tolerance, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day. 

Meningitis 100 mg/kg/day (not to exceed 4 g). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 g/day) is recommended. May give daily dose once per day or in equally divided doses every 12 hours. Usual duration is 7 to 14 days. 

IV Following induction, the recommended maintenance dose is 5 mg/kg given as a constant rate IV infusion over 1 hour once per day 7 days per week, or 6 mg/kg once per day 5 days/week. 

Absorption of an oral dose of betaxolol (Kerlone, Betoptic) is almost complete. The drug is subject to a slight first-pass effect such that the absolute bioavailability of the drug is about 90%. Approximately 50% of administered betaxolol binds to plasma proteins, and its plasma half-life is about 20 hours it is suitable for dosing once per day. The primary route of elimination is by liver metabolism, with only 15% of unchanged drug being excreted. 

Carteolol (CartroJ) is a long-acting (3-blocker that is suitable for dosing once per day. It is almost completely absorbed and exhibits about 30% binding to plasma proteins. Unlike many (3-blockers, carteolol is not extensively metabolized. Up to 70% of an administered dose is excreted unchanged. 

Nadolol (Corgard) is slowly and incompletely absorbed from the gastrointestinal tract, and only 30% of an orally administered dose is absorbed. Appreciable metabolism does not seem to occur nadolol is excreted primarily unchanged in the urine and feces. The plasma half-life is quite long, approaching 24 hours, which permits dosing once per day. 

Non-radiolabelled diethanolamine was applied to the dorsal skin of rats (1500 mg/kg bw, ca. 20 mg/cm to 25 cm of skin and covered) once per day for 6 h per day for three or six days. [ C]Diethanolamine (1500 mg/kg bw) was then applied to the skin for a 48-h penetration test. Animals in the three-day and six-day pretreatment groups absorbed 21% and 41% of the applied dose, respectively. Liver, kidney or carcass contained the majority of absorbed radioactivity, urine from three-day and six-day groups contained 4.3% and 13%, respectively, and less than 0.3% was found in brain, fat or heart (Waechter et al, 1995, cited by Knaak et al, 1997). 

The effectiveness of sertraline in pediatric patients (ages 6 to 17 years) with OCD was demonstrated in a 12-week, double-blind, placebo-controlled study ( 150). Patients were initiated at a dose of either 25 mg per day (ages 6 to 12 years) or 50 mg per day (ages 13 to 17 years) and then adjusted over the next 4 weeks to a maximal dose of 200 mg per day as tolerated. The mean dose of completers was 178 mg per day. Dosing was once a day, either morning or evening. No differences in efficacy based on age or gender were observed. 

Groups of 50 male and 50 female Swiss mice, nine weeks of age, were administered 100 (low-dose) or 500 (high-dose) mg/kg bw dichloromethane (purity, > 99.9%) in olive oil by gavage once per day on four to five days per week for 64 weeks. Groups of 60 mice of each sex were given olive oil (vehicle-control). Animals were then kept under observation for their lifespan. Excess mortality was observed in male and female mice exposed to the high dose p < 0.01). An increase in mortality appeared after 36 weeks of treatment and led to withdrawal of the treatment at 64 weeks. In mice that died by 78 weeks, the incidence of lung tumours in males was 1/14 control, 4/21 low-dose and 7/24... 

The LMWHs appear to be as effective as unfractionated (mixed) heparins, but they offer certain advantages. For example, LMWHs can be administered by subcutaneous injection into fat tissues, thereby decreasing the need for repeated intravenous administration. Subcutaneous administration offers an easier and more convenient route, especially for people who are being treated at home or as outpatients.98 118 Dosing schedules of LMWHs are typically easier (once per day), compared to 2 or more daily injections of unfractioned heparin.132 The anticoagulant effects of LMWHs are also more predictable, and... 

Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil retrospective analysis of data from placebo-controlled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing, Am J Cardiol 2006 97 1778-1784. 

Reviews of clinical studies with fosinopril in the treatment of essential hypertension (151,152) and heart failure (153,154) are available. It is approved for both indications in the United States and is used in antihypertensive therapy at a recommended initial dose of 10 mg once per day, which may be increased to 80 mg once per day. For the treatment of heart failure, the initial dose is also 10 mg, which is often increased to a maintenance dose of 20-40 mg once per day. 

Bucci et al. (1991) and Bucci and Parker (1992) conducted range-finding smdies with GB Type I (GB containing tributylamine as a stabilizer) and GB Type II (GB containing diisopropylcarbodiimide as a stabilizer). The chemicals were administered by gavage once per day, 5 days per week for 3 weeks. These studies indicated that for both GB mixtures, the maximum tolerated dose was 0.3 mg/kg/day and a dose of 0.5 mg/kg/day was lethal to the test animals. 

The subchronic rat study conducted by Bucci and Parker (1992) with GB Type II is used here to derive an oral RfD for GB. This study is described in detail in Section 3.3. Briefly summarized, the results of this smdy showed smtistically significant (p <0.05) decreases in plasma and RBC-ChE activity levels in male and female CD rats dosed by gavage once per day, 5 days per week for 13 weeks. The RBC-ChE levels are shown in Table 4. Significant reductions in RBC-AChE relative to controls and to baseline values were seen in male rats in all dose groups (Appendix B). Although no other toxic effects were observed in the rats dosed with GB Type II, brain lesions (hippocampal necrosis) occurred in rats dosed with GB Type I (in 1 of 12 females dosed with 0.075 mg/kg/day, and in 2 of 12 females dosed with 0.3 mg/kg/day, but in none of the females dosed with 0.150 mg/kg/day, and in the of the males dosed with 0.075, 0.15, or 0.3 mg/kg/day) (Bucci et al., 1991). The absence of effects at the mid-dose, and the possibility that post-mortem autolysis contributed to the findings (see section 3.3) makes it difficult to select a LOAEL or NOAEL for this endpoint. 

The snbchronic rat study conducted by Bucci et al. (1992a) is used here to derive an oral RfD for GD. This stndy is described in detail in section 3.2. Briefly summarized, the results of this study showed statistically significant (p <0.05) decreases in plasma-ChE activity levels in male and female CD rats dosed by gavage once per day, 5 days per week for 13 weeks. There were no definitive dose-related changes in RBC-ChE, and NTE levels were not significantly affected by the GD treatment. 

Dosing schedule once per day, five days per week. 

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