Inputs_and_calculations

Inputs and calculations

Like Wagner-Nelson, the Loo-Riegelman method estimates the fraction of drug absorbed as a function of time, relative to the total amount to be absorbed, following the method described in Gibaldi and Perrier (1975) pages 136 to 142. It computes AUC values for each time point in the time-concentration dataset, as in Wagner-Nelson. For Loo-Riegelman, estimates for K10, K12, and K21 must be provided, as may be obtained by running Least-Squares Regression PK model 7 on separate IV data.

Note: Loo-Riegelman computations assume single-dose PK data with a concentration value of zero at dose time. If no concentration value exists at dose time, a value of zero is used.

The value of AUCINF (AUC_¥) may be user-specified or can be computed as for non-compartmental analysis:

AUC_¥=AUC_last+C_last/Lambda_z

Either the observed or predicted value for C_last, where C_{last_pred}=exp(intercept – Lambda_z*t_last), can be used. As in the Wagner-Nelson method, the method for computing Lambda Z is selected: best fit, user-specified range, or user-specified value. An intercept for the last case can be entered. If the intercept is not specified, it will be computed using the last positive concentration and associated time value:

intercept=Lambda_z * t_last+ln(C_last)

Note that the Loo-Riegelman method uses Lambda Z only to compute AUC_¥; it uses the intercept only to compute C_{last_pred}.

The cumulative amount absorbed at time t, normalized by the central compartment volume V1, is:

Cumul_Amt_Abs_V(t)=Conc(t)+K₁₀ * AUC(t)+Amt_Peripheral_V(t)

The amount in the peripheral compartment at time t, normalized by V1, is computed sequentially as:

Amt_Peripheral_V(t)=(Prior_Amt_Peripheral_V) * exp(–K21* dt)
+ (K12 * Prior_Conc/K21) * (1 – exp(–K21* dt)
+ (K12 * dt * dConc/2)5

See Gibaldi and Perrier (1975) pages 138–139 for the derivation of this equation.

Cumul_Amt_Abs_V at time infinity is:

Cumul_Amt_Abs_V(inf)=K₁₀ * AUC_¥

The fraction absorbed at time t is computed as:

Rel_Fraction_Abs(t)=Cumul_Amt_Abs_V(t)/Cumul_Amt_Abs_V(inf)

Data points with a missing value for either time or the concentration will be excluded from the analysis and will not appear in the output.