Nominal dose

The first study to demonstrate the activity of enfuvirtide in HIV-infected patients (Kilby et al. 1998) showed that patients receiving the maximum 100 mg intravenous dose had maximum median declines in HIV-1 RNA of -1.96 logjo copies/mL through 14 days. Several additional studies (Kilby et al. 2002 Lalezari et al. 2003a, b) further demonstrated the safety and efficacy of enfuvirtide and led to the selection of twice-daily subcutaneous injections of a 90 mg nominal dose for testing in the TORO (T-20 vs. optimized regimen only) pivotal clinical trials. 

It has been shown that the maximal in vitro FPF of most marketed devices is between approximately 20 and 50% of the nominal dose, but the maxima are achieved at different flow rates [109,110]. Lung depositions from a great number of DPI studies, summarized in two review articles [112,135], show that most systems have the same efficacy as MDIs (between 5 and 20% of the metered dose) with a few exceptions, such as the Easyhaler , Turbuhaler and Novolizer , which yield lung depositions between 20 and 30% of the dose, or even higher [135-137]. 

The two machines are very similar in terms of average drug content for the tablets, both producing tablets with a mean very close to 250 mg. However, the two products clearly differ. With the Alpha machine, there is a considerable proportion of tablets with a content differing by more than 10 mg from the nominal dose (i.e. below 240 mg or above 260 mg), whereas with the Bravo machine, such outliers are much rarer. An indicator of dispersion is required in order to convey this difference in variability. 

Finlay, Stapleton, and Zuberbuhler recently tested 15 different jet nebulizers available commercially to investigate the performance of nebulizers. The drug compound used in the study was a 2.5 ml unit dose of Ventolin (containing 1 mg/ml of salbutamol sulfate), which corresponds to a 2.5 mg in nominal dose per drug container. Table 3 shows the experimental results for the different nebulizers. 

Nominal dose (metered dose) The dose represents the actual amount of the drug loaded into the pMDI device. It can be calculated using drug concentration times the metering valve volume... 

The nominal dose is defined as the amount of active drug metered as a liquid solution from the device. The emitted dose is the amount of aerosolized drug obtained at the exit of the mouthpiece, and the device delivery efficiency is the ratio of the emitted to nominal dose. The mean delivery efficiency was approximately 94% (SD = 3.2) with a 3.4% coefficient of variation. The delivery efficiency for the two devices tested was 93% (SD = 3.60, n = 5) and 95% (SD = 2.8, n = 5), respectively. The intradevice variation was 1.7% (coefficient of variation, n = 2 prototypes). There were no significant differences p > 0.05) in the drug mass output within the device throughout its life cycle, nor between devices tested in the study. 

Device II) Actuation number Nominal dose (Eg) Emitted dose (Eg) Device delivery efficiency (%)... 

DPI and three different doses using the EHD device. The nominal doses were 1000 pg for the DPI and 150, 250, and 400 pg for the EHD device. Multiple blood samples were collected from each subject up to 8 h after dosing to measure plasma drug concentration. An interval of 1 week was used between administration of the four doses. 

AERx Mechanical, battery powered 2-4 pm 50-72% of nominal dose 53% of loaded dose... 

AeroDose Vibrating orifice 2.0 pm 80% of nominal dose 70% of emitted dose... 

To demonstrate that the product delivers nominal dose at the end of label claim (can be derived from CU data)... 

Figure 2 Relationship between deposition of a radiolabeled DPI aerosol and the measured fine particle dose of the labeled powder inhaled for each subject. Both variables are expressed as the percent of nominal dose. The correlation is higher for the lower flow rate used to inhale the powder, possibly due to the more consistent amount of drug deposited in the oropharynx. (From Ref. 88.)...

Fig. 5 [86] shows an example of the mean unit spray content for drug and radioactivity for several study days using this labeled powder. Each bar of the graph represents a mean standard deviation of 10 unit doses. While the CV of the daily measurements for both dmg and radioactivity must be within specified limits, it should be understood that the mean daily level of radioactivity in the formulation or nominal dose of radioactivity varies as a function of the level of the specific activity available from the generator on the day of the study. This variability in the amount of radioactivity affects only the absolute dose of radioactivity inhaled and not the measured deposition distribution. Deposition results should be normalized to account for these differences, even for the small, day-to-day variability in the supply of radioactivity. 

Figure 7 Deposition in the lung, the oropharynx, and the sum of the oropharynx and gut, expressed as the percent of nominal dose, plotted against the impaction parameter, d2Q, where d is particle size and Q is inspiratory flow rate [99]. With this particular inhaler, a fourfold difference in Q caused a marked shift in the distribution of drug between lung and oropharynx + gut. Variability in deposition seen between subjects may be reduced by controlling the particle size of the inhaled drug and the inspiratory flowrate during the inhalation maneuver.

The AUCs can be obtained by administration of intravenous and oral formulations in a crossover study. It is important to use the exact dose rather than nominal doses the oral and intravenous formulations should be assayed, and the syringes or giving sets used for the intravenous administration carefully weighed before and after dosing. The size of the intravenous dose should be reduced compared with the oral dose in proportion to the expected bioavailability so that the AUCs will be similar. This avoids assumptions about linear kinetics and maximises safety, since high plasma concentrations by the intravenous route are avoided. Similarly, it is appropriate to infuse the intravenous drug over a period comparable with the time to maximum concentration (T j g ) after oral administration in order to avoid transient high peaks. 

FIGURE 6.1 A simulated nonadherence concentration profile for a subject over 16 nominal doses. The dosing pattern for the patient is described in the upper half of the figure. Each solid bar represents an actual dosing time, and each dotted bar a scheduled dosing time. The height of the solid bar can be 1 - one dose taken, 2 - two doses taken, and 1 (i.e., M in the figure)—a dose missed or not taken. 

Individuals are assumed to arise randomly from one of two subpopulations with MDMM. Subjects with PK data compatible with the nominal dose history comprise... 

PTIM = Time of previous pain observation DOSE = nominal dose amount... 

QUIT = Indicator of remedication (0=stay in study l=quit study) PTIM = Time of previous pain observation DOSE = nominal dose amount... 

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