Computation method

Given the concentration data points C(ti) at times ti, (i=1,2,…,n), after a single dose D, one may obtain the concentration C(t) at any time t through interpolation if t1 < t <tn, or extrapolation if t > tn. The extrapolation assumes a log-linear elimination process; that is, the terminal phase in the plot of log(C(t)) versus t is approximately a straight line. If the absolute value of that line’s slope is lZ and the intercept is ln(b), then C(t) = bexp(–lZt) for (t > tn).

The slope lZ and the intercept are estimated by least squares from the terminal phase; the time range included in the terminal phase may be specified or, if not specified, estimates from the best linear fit (based on adjusted R2 as in the Best Fit method in Noncompartmental Analysis) will be used. The half life is: ln(2)/lZ

Suppose there are m additional doses Dj, j = 1,…,m, and each dose is administered after t j time units from the first dose. The concentration due to dose Dj will be:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2181

where t is time since the first dose and C(ttj) = 0 for t £ tj.

The total predicted concentration at time t will be:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2183

If the same dose is given at constant dosing intervals t, and t is sufficiently large that drug concentrations reflect the post-absorptive and post-distributive phase of the concentration-time profile, then steady state can be reached after sufficient time intervals. Let the concentration of the first dose be C1(t) for 0 < t < t, so t is greater than tn. Then the concentration at time t after nth dose (i.e., t is relative to dose time) will be:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2185

As Phoenix_UserDocs_NonParametric_Superposition_Object_image2187, the steady state (ss) is reached:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2189

To display the concentration curve at steady state, Phoenix assumes steady state is at ten times the half life.

For interpolation, Phoenix offers two methods: linear interpolation and log-interpolation. Linear interpolation is appropriate for log-transformed concentration data and is calculated by:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2191

Log-interpolation is appropriate for original concentration data, and is evaluated by:

Phoenix_UserDocs_NonParametric_Superposition_Object_image2193

For additional information see Appendix E of Gibaldi and Perrier (1982). Pharmacokinetics, 2nd ed. Marcel Dekker, New York.


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