Maximal recommended therapeutic dose

Maximal recommended therapeutic dose (MRTD as defined by the US FDA) has been correlated with potential toxicity. Matthews et al. have reported in silico multicase models for MRTD [55]. According to their analysis, more toxic molecules will have MRTD values less than 2.7 mg/kg/day and less toxic molecules will have MRTD more than 4.99 mg/kg/day. If one builds an in silico model for MRTD, then a new rule can be added to the computational alert AD ME rules described above. 

Starting doses should be in the range of 25 to 50 mg/day and titrated up slowly to minimize hypotension. The usual therapeutic range is 300 to 500 mg/day (the recommended maximal dose is 900 mg/day). The usual therapeutic dose is typically achieved in 2 to 5 weeks and should be maintained for several more before considering an increase. In this context. Perry and colleagues found a therapeutic threshold clozapine plasma level of 350 ng/mL (i.e., 64% with levels above this responded, versus only 22% with levels below this point), which required an average dose of 380 mg/day ( 66). 

THERAPEUTIC USES Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children, but tolerance to its antiseizure effects usually develops within 1-6 months, after which some patients will not respond to clonazepam at any dosage. The initial dose of clonazepam for adults should not exceed 1.5 mg/day and for children 0.01-0.03 mg/kg/day. Dose-dependent side effects are reduced if two or three divided doses are given each day. The dose may be increased every 3 days in amounts of 0.25-0.5 mg/day in children and 0.5-1 mg/day in adults. The maximal recommended dose is 20 mg/day for adults and 0.2 mg/kg/day for children. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

Combination therapy - For maximal therapeutic effect in combination with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is 3 tablets taken twice daily with meals or 6 tablets taken once daily with a meal. Doses of 4 to 6 tablets/day have been shown to be safe and effective when coadministered with an HMG-CoA reductase inhibitor or when the 2 drugs are dosed apart. 

Whereas many CNS safety tests evaluate multiple doses, we recommend the inclusion of just two doses for non-precipitated withdrawal studies. The low dose should be close to the dose inducing clear effects in the test predictive of the substance s therapeutic indication. The high dose should be the maximally tolerated dose as determined, for example, from an Irwin test. If it can be shown that the test substance can be repeatedly administered at a maximally tolerated dose under conditions where similar treatment with an appropriately chosen reference substance induces... 

An initial dose of 1 mg is recommended. Doses are titrated upward depending on the therapeutic response 10 mg/day may be required for maximal effect in BPH. 

Low-dose methotrexate, 10 to 25 mg a week, is used for the treatment of cutaneous sarcoidosis (42). Cutaneous improvement may be noted within one month, but maximal therapeutic benefit often does not occur until at least six months after the initiation of treatment. The drug requires careful monitoring of liver function tests and blood cell counts. Folic acid is recommended to be given in conjunction with methotrexate. Approximately 10% of sarcoidosis patients taking methotrexate develop hepatic fibrosis, even if their serum liver function tests are normal (43). Therefore liver biopsies should be considered after two grams of total therapy (usually after two years) (43). 

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