Maintenance dose defined

Thus, the regimen would be a loading dose of 10.5 mg/ kg, followed by maintenance doses of 7.5 mg/kg every 5.41 hours. This regimen is not only impractical but, were it carried out, it would produce Cmax and Cmm concentrations too close to the limiting values to allow for any errors. A better approach would be to define clinicially relevant Cmax and Cm n values and use the approach in the previous section to develope a useful dosing regimen. 

The maintenance dose may be defined as the size of the dose required to maintain the therapeutic range according to the dosage regimen. The maintenance dose needed to replace the amount lost over the dosing interval is the difference between the loading dose and the amount remaining at the end of the interval. It is calculated as,... 

In 16 patients with treatment-resistant schizophrenia (defined as non-responsiveness to at least three antipsychotic drugs from at least two different chemical classes), olanzapine was effective treatment in a significant proportion no serious adverse events were associated with maintenance doses of 10-40 mg/day, and no subjects dropped out (26). 

The safety and tolerability of once-daily oral metrifonate has been evaluated in patients with probable mild to moderate Alzheimer s disease in a randomized, doubleblind, placebo-controlled, parallel-group study (9). Metrifonate was given to 29 patients as a loading dose (2.5 mg/kg) for 2 weeks, followed by maintenance dose (1 mg/kg) for 4 weeks 10 patients received placebo. The proportion of patients who had at least one adverse event was comparable in the two groups metrifonate 76%, placebo 80%. Selected adverse events, defined as those for which the incidence in the metrifonate and placebo group differed by at least 10%, were diarrhea, nausea, leg cramps, and accidental injury. The adverse events were predominantly mild and transient. Those who took metrifonate had a significantly lower heart rate. Metrifonate had no clinically important effect on laboratory tests, such as liver function tests, and did not affect exercise tolerance or pulmonary function. 

Considerable efforts have been devoted to defining the optimal dose to ensure minimal toxicity while retaining efficacy. In transplant patients, the daily maintenance dose is 2-6 mg/kg/day. In non-transplant patients, daily doses of 2.5 mg/kg up to a maximum of 4 mg/kg are usually recommended. 

Another, more recent, example is enzyme therapy for Gaucher s disease, an inborn error of metabolism, treated with Ceredase. The therapy, which requires more than a ton of placenta annually to extract and make the drug, can cost as much as S500,000 per year per person, depending on the dosage needed. A 1996 National Institutes of Health technology assessment panel addressed issues in diagnosis and treatment of the disease and concluded that despite the success of enzyme therapy, treatment is limited by the cost. The panel reported that it was imperative to define the appropriate clinical indications for treatment and to determine the lowest effective initial and maintenance doses (43). 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

An adequate trial of antidepressant medication is defined as treatment with therapeutic doses of a drug for a total of 4 weeks. After 4 weeks of antidepressant treatment, patients can be divided into three groups those who have achieved a full response, those who have achieved a partial response, and those who have not responded. In the case of patients who achieve full remission, treatment should continue for a minimum of 4-6 months, or longer if the patient has a history of recurrent depression (see Maintenance Treatment of Major Depression later in this chapter). If a partial response has been achieved by 4 weeks, a full response may be evident within an additional 2 weeks without further intervention. If the symptoms do not respond at all, the dose should be increased, a different antidepressant should be used, or the therapy should be augmented with another medication (see Treatment-Resistant Depression later in this chapter). 

Ideally, any series of toxicological investigations should attempt to define the following the nature of the harmful effects, ie, the basic injury produced the incidence and severity of the effects as functions of the exposure dose the mechanisms by which the effects are produced, ie, the fundamental biological interactions and consequent biochemical and biophysical aberrations which are responsible for the initiation and maintenance of the toxic responses the detection of the effects, ie, the development of methodologies for the specific recognition and quantitation of the toxic effects and whether there is reversibility of the toxic injury. This may involve a determination of whether spontaneous resolution of injury, ie, healing, occurs after cessation of exposure, or if it is possible to induce reversibility of toxic injury by antidotal or other measures, ie, treatment. 

The time for antidepressant onset of effect in BN is unclear. In the absence of data, the definition of a therapeutic trial from the depression hterature (4 to 8 weeks at a therapeutic dose) should be used. Since the majority of subjects will not experience a complete remission, and there are few data on predictors of response or whether switching to another class will improve response, a clear and specific target should be stated initially. Eor example, will the medication be continued if the patient has a 50% reduction in binge-purge episodes, or if abstinence from such behavior is the ultimate therapeutic goal. Optimal duration of treatment after response is also poorly defined. Most clinicians will treat for 6 months to 1 year and then re-evaluate the need for ongoing treatment. The evidence is mixed as to whether any early benefit is sustained, hence the decision to continue treatment should be made based on both initial response and the maintenance of that benefit. If the symptoms return within a few months after the antidepressant is discontinued, then the treatment may need to be reinitiated. 

Interpatient variability in the pharmacokinetics of oral methotrexate and mercaptopurine may also be an important determinant of the effectiveness and toxicity of maintenance therapy. Patients who take their oral methotrexate and mercaptopurine on an evening versus a morning schedule appear to have a superior outcome. To account for the interpatient variability, most pediatric protocols titrate the dose of either agent to maintain an absolute neutrophil count of 750 to 1,500/rmn. Some protocols circumvent bioavailabihty and poor compliance issues by administering methotrexate parenterally. The importance of these pharmacokinetic issues in adults is less well defined. 

Unlike other subtypes of AML, the role of maintenance therapy is well defined in APL. Before the advent of tretinoin, nonrandomized trials supported a benefit of continnons low-dose methotrexate and mercaptopurine in prevention of relapse of APL. Larger prospective trials have demonstrated decreased relapse rates in patients who received maintenance therapy (either tretinoin or combination chemotherapy), and some trials have demonstrated increased EFS and OS. ° In a smdy that compared maintenance with tretinoin, tretinoin plus chemotherapy, and chemotherapy or observation, observation was associated with the highest relapse rate and tretinoin plus chemotherapy with the lowest relapse rate. Current recommendations for maintenance therapy in adult APL patients includes tretinoin 45 mg/m per day for 15 days every 3 months, in addition to mercaptopurine 100 mg/m orally daily and methotrexate 10 mg/m per week, for 2 years in aU... 

The maintenance programme and operational tasks should be defined, preferably on the basis of well established concepts. The number of staff for each task should be based only on the operational requirements and should not be artificially increased to comply with the regulatory requirements or the dose constraints. For tasks for which doses are predicted to be relatively minor, the work can be expressed generically in terms of the number of person-hours that will be spent in each radiation zone. The type of worker who will perform each task is also identified. Types of worker include maintenance personnel, in-service inspection personnel, electrical staff, support staff (e.g. scaffolders), decontamination staff and health physics staff. 

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