Therapeutic dose formulation, administration

Preclinical and clinical pharmacokinetics studies with a new drug indicate systemic exposure after administration of the therapeutic dose formulation. Thus, even if there is an interaction from an established or new excipient, adequate safety evaluation can be assessed. However, it would be useful to demonstrate to a regulator that possible interference of the active drug by the rest of the formulation had been considered. If an excipient is added to the new drug form for an active role, the proposed mechanism of action will need to be discussed carefully. 

Figure 3.5 Pl< profile of a compound with hERC inhibition with an IC50 between 20-30 XM. The effective plasma concentration is 10 xM. The single dose produced a spike of over 30 xM plasma concentration, not required for therapeutic effect but for a sufficient level 12 hours after administration. However, the associated with this dose/formulation reached the level when hERG inhibition occurs.

The difficulty in determining dose delivered with oral administration of high-dose busulfan in preparative regimens for hematopoietic stem cell transplantation results in lethal toxicity due to overdosing and increased potential for relapse with recurrent disease. Oral pharmacokinetic studies ineffectively determine proper AUC for reliable establishment for a proper therapeutic dose. Studies with IV formulations have demonstrated that all patients are evaluable. With the development of a limited sampling strategy to analyze proper AUC over intermittent time periods, improved patient risk profiles for busulfan have been implemented in clinical practice. 

After oral doses of 50-200 mg, sertraline reaches a maximum plasma concentration in 4.5-8.4h. Administration of the oral concentrate results in a higher area under the curve (AUC) and Cmax compared to the oral tablet. Peak absorption may be delayed with large ingestions. When food was administered with therapeutic doses of tablet formulation, both the peak and total plasma levels (AUC) increased however, the time to reach peak plasma concentration decreased. With repeated dosing, a steady-state plasma level should be achieved within 7 days. 

Dideoxyinosine (DDI) is a therapeutic agent used in the treatment of AIDS. DDI is known to be easily hydrolyzed in the presence of acid. To aid in the selection of a vehicle for administration of DDI in planned toxicological evaluations, the bioavailability of DDI was determined in B6C3F1 mice of both sexes after intragastric administration in buffered and unbuffered formulations (R. Handy, personal communication, January 11, 1994). The significant effect of vehicle pH on the absorption of DDI was demonstrated by comparison of plasma DDI concentrations from buffered versus unbuffered oral dose formulations. The bioavailability... 

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

Blood levels therapeutic level is 10-20 mcg/ml toxicity may occur with small increase above 20 mcg/ml and occasionally at levels below this obtain serum levels 1-2 hr after administration for immediafe-release products and 5-9 hr after the am dose for sustained-release formulations... 

Naltrexone is generally taken once a day in an oral dose of 50 mg for treatment of alcoholism. An extended-release formulation administered as an IM injection once every 4 weeks is also effective. The drug can cause dose-dependent hepatotoxicity and should be used with caution in patients with evidence of mild abnormalities in serum aminotransferase activity. The combination of naltrexone plus disulfiram should be avoided, since both drugs are potential hepatotoxins. Administration of naltrexone to patients who are physically dependent on opioids precipitates an acute withdrawal syndrome, so patients must be opioid-free before initiating naltrexone therapy. Naltrexone also blocks the therapeutic effects of usual doses of opioids. 

The therapeutic administration of biologic hormones should, ideally, mimic the endogenous secretion patterns of the hormone to achieve optimal effects. Hormone formulations and dosing regimens have been developed to reflect the normal time-course of exposure to the hormone. In some cases, the effects of the hormone can be highly dependent on the dose schedule. These important aspects of the exposure-response relationships for hormones are illustrated here for insulin and parathyroid hormone. 

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