Patient-specific dosimetry

• US 20050288869A1
• Filed: 08/10/2005
• Published: 12/29/2005
• Est. Priority Date: 06/04/1998
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GSK plc), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Smithkline Beecham Corporation (GSK plc), Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Kroll, Stewart M., Wahl, Richard L., Zasadny, Kenneth R., Siegal, Jeffry A.
• Granted Patent: US 7,668,662 B2
• Time in Patent Office: Days
• US Class Current: 702/19
• CPC Class Codes: A61K 51/1069 the tumor cell being from blood cells, e.g. the cancer being a myeloma

Abstract

A patient-specific optimally effective radiation dose for administration of a radiopharmaceutical to a patient for treatment of a disease may be established by basing the calculation of the appropriate therapeutic dose on factors such as the desired total body dose, the maximum tolerated dose, the typical clearance profile of the radiopharmaceutical, the patient'"'"'s mass or maximum effective mass, and the patient-specific residence time of the radiopharmaceutical or an analog in the whole body of the patient. The use of the method allows for treatment of a patient with an appropriate dose which is maximally effective against the disease yet minimally toxic. The determination of a patient-specific therapeutic dose may be assisted by the use of a software program set to the particular parameters of the radiopharmaceutical.

Claims

1. A method of establishing a patient-specific therapeutic dose for administration of an ¹³¹I-labeled anti-B1 antibody radiopharmaceutical to a patient, the method comprising:

determining a maximum tolerated dose for the radiopharmaceutical;

determining a desired total body dose (TBD) of the radiopharmaceutical for the patient;

administering to the patient a trace dose of a radiopharmaceutical or an analog of the radiopharmaceutical;

determining a clearance profile for the radiopharmaceutical or the radiopharmaceutical analog;

determining the patient'"'"'s mass and maximum effective mass;

selecting the lower of the patient'"'"'s mass and maximum effective mass;

determining activity hours (AH) for the radiopharmaceutical or radiopharmaceutical analog with the following equation (Equation

     1);

$\begin{array}{cc}\mathrm{AH}=\frac{\mathrm{TBD}\times <br><br>\left(M<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{or}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{MEM}\right)}{\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]}<br><br><br><br>\mathrm{where}<br><br>\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]& \left(\mathrm{Equation}<br><br>\text{\hspace{1em}<br><br>}<br><br>I\right)\end{array}$

in Equation I represents the sum of electron energy and photon energy deposited in the total body of the patient by the radiopharmaceutical or radiopharmaceutical analog and said determining activity hours uses the lower of the patient'"'"'s mass (M) or maximum effective mass (MEM);

determining residence time of said administered trace dose of the radiopharmaceutical or the radiopharmaceutical analog in the whole body of the patient, the residence time being correlated to the clearance profile; and

establishing the patient-specific dose of the radiopharmaceutical for the patient by solving for therapeutic dose in the following equation;

$\mathrm{therapeutic}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}=\frac{\mathrm{Activity}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{Hours}}{\mathrm{Residence}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{time}}\times <br><br>\frac{\mathrm{desired}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{total}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{body}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}}{\mathrm{maximum}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{tolerated}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}}.$

2. A method according to claim 1, wherein the step of determining the activity hours via Equation I comprises obtaining activity hours from a table or database that has been prepared using Equation I.

3. A method according to claim 1, wherein the step of determining the maximum tolerated dose comprises performing a dose escalation study for the radiopharmaceutical in a patient population.

4. A method according to claim 1, wherein the maximum effective mass is based solely on the gender and height of the patient.

5. A method according to claim 1, wherein the step of determining the clearance profile comprises performing a study following measurement over time of the loss of radioactivity from an administered radiopharmaceutical.

6. A method according to claim 1, wherein the step of determining the clearance profile comprises performing a dose escalation study for the radiopharmaceutical.

7. A method according to claim 1, wherein the clearance profile provides an activity-time curve shape for the radiopharmaceutical.

8. A method according to claim 1, wherein the step of determining the residence time for the radiopharmaceutical comprises:

making measurements of radioactivity in the whole body of the patient at each of a number of time points,

calculating percent injected activity of the radiopharmaceutical at each of the time points, and

establishing the residence time by plotting the time points vs. percent injected activity on a semilog graph and determining the time at 37% injected activity.

9. A method according to claim 8, wherein the measurements of each time point is background corrected.

10. A method according to claim 8, wherein the number of time points are correlated to the clearance profile of the radiopharmaceutical so that at least 2 measurements are made if the radiopharmaceutical has monoexponential clearance, at least 4 measurements are made if the radiopharmaceutical has biexponential clearance, and at least 6 measurements are made if the radiopharmaceutical has triexponential clearance.

11. A method according to claim 1, wherein the step of determining the residence time for the radiopharmaceutical comprises:

making measurements of radioactivity in the whole body of the patient at each of three time points and solving for residence time with the following equation;

$\mathrm{Residence}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{time}<br><br>\text{\hspace{1em}<br><br>}<br><br>\left(\mathrm{hr}\right)=\frac{t_2<br><br>\left(1-\frac{C_2}{C_1}\right)}{{\log }_e<br><br>\text{\hspace{1em}<br><br>}<br><br>\left(\frac{C_1}{C_2}\right)}+\frac{\frac{C_2}{C_1}<br><br>\left(t_3-t_2\right)}{{\log }_e<br><br>\left(\frac{C_2}{C_3}\right)}$

where t₁, t₂, and t₃ are the three time points and c₁, c₂, and C₃ are the counts at each of the t₁, t₂, and t₃ time points.

12. A method according to claim 1, wherein the step of determining the residence time for the radiopharmaceutical comprises:

making measurements of radioactivity in the whole body of the patient at each of a number of time points, and solving for T in the following equation;

$\mathrm{\tau <br><br>}=\frac{\underset{i=1}{\overset{n}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>\frac{a_i}{{\mathrm{\alpha <br><br>}}_i}}{\underset{i=1}{\overset{n}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>a_i}$

where τ

is residence time, n is the number of exponential terms as determined by the clearance profile, a_i are the intercepts, and α

_i are the slopes of the ith exponential term when plotted on a log-linear graph with percent injected activity plotted on the y-axis and time on the x-axis.

13. A method according to claim 12, wherein the number of time points are correlated to the clearance profile of the radiopharmaceutical so that at least 2 measurements are made if the radiopharmaceutical has monoexponential clearance, at least 4 measurements are made if the radiopharmaceutical has biexponential clearance, and at least 6 measurements are made if the radiopharmaceutical has triexponential clearance.

14. A method according to claim 1, wherein the step of determining the residence time for the radiopharmaceutical comprises:

making measurements of radioactivity in the whole body of the patient at each of a number of time points, generating an activity-time curve, and using the trapezoidal rule or Simpson'"'"'s rule to determine the residence time.

15. A method according to claim 1, wherein said maximum effective mass is a multiple of a calculated lean body mass, said multiple having been determined from empirical data gathered from dose escalation studies in a patient population to which said patient belongs.

16. A method according to claim 15, wherein said multiple is 1.37.

17. A method of establishing a patient-specific dose for administration of an ¹³¹I-labeled anti-B1 antibody radiopharmaceutical to a patient, the method comprising:

determining a clearance profile for the radiopharmaceutical or a radiopharmaceutical analog, said clearance profile providing a minimum number of time points for determination of the patient-specific residence time of the radiopharmaceutical or the radiopharmaceutical analog;

determining the desired total body dose (TBD) of the radiopharmaceutical for the patient;

determining the patient'"'"'s mass (M) and maximum effective mass (MEM);

selecting the lower of the patient'"'"'s mass and maximum effective mass (M or MEM);

determining the activity hours (AH) for the radiopharmaceutical or a radiopharmaceutical analog with Equation I using the lower of the patient'"'"'s mass and maximum effective mass (M or MEM);

$\begin{array}{cc}\mathrm{AH}=\frac{\mathrm{TBD}\times <br><br>\left(M<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{or}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{MEM}\right)}{\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]}<br><br><br><br>\mathrm{where}<br><br>\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]& \left(\mathrm{Equation}<br><br>\text{\hspace{1em}<br><br>}<br><br>I\right)\end{array}$

in Equation I represents the sum of electron energy and photon energy deposited in the total body of the patient by the radiopharmaceutical or radiopharmaceutical analog;

determining the patient-specific residence time of an administered tracer dose of the radiopharmaceutical or the radiopharmaceutical analog in the whole body of the patient; and

establishing a therapeutic dose of the radiopharmaceutical for the patient by dividing the activity hours by the patient-specific residence time to obtain an initial therapeutic dose and optionally multiplying the initial therapeutic dose by an attenuation factor, said attenuation factor being determined by the TBD divided by the maximum tolerated dose for the radiopharmaceutical.

18. A method according to claim 17, wherein the step of determining the residence time for the radiopharmaceutical comprises:

making measurements of radioactivity in the whole body of the patient at each of a number of time points, and solving for τ

in the following equation;

$\mathrm{\tau <br><br>}=\frac{\underset{i=1}{\overset{n}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>\frac{a_i}{{\mathrm{\alpha <br><br>}}_i}}{\underset{i=1}{\overset{n}{\sum <br><br>}}<br><br>\text{\hspace{1em}<br><br>}<br><br>a_i}$

where τ

is residence time, n is the number of exponential terms as determined by the clearance profile, a_i are the intercepts, and α

_i are the slopes of the ith exponential term when plotted on a log-linear graph with percent injected activity plotted on the y-axis and time on the x-axis.

19. A method according to claim 18, wherein the number of time points are correlated to the clearance profile of the radiopharmaceutical so that at least 2 measurements are made if the radiopharmaceutical has monoexponential clearance, at least 4 measurements are made if the radiopharmaceutical has biexponential clearance, and at least 6 measurements are made if the radiopharmaceutical has triexponential clearance.

20. An ¹³¹I-labeled anti-B1 antibody radiopharmaceutical composition ready for administration to a patient, comprising a predetermined amount of said ¹³¹I-labeled anti-B1 antibody in a pharmaceutical carrier, wherein said amount is determined by a method comprising:

determining a maximum tolerated dose for the radiopharmaceutical;

determining a desired total body dose of the radiopharmaceutical for the patient;

administering to the patient a trace dose of the radiopharmaceutical or an analog of the radiopharmaceutical;

determining a clearance profile for the radiopharmaceutical or the radiopharmaceutical analog;

determining the patient'"'"'s mass and maximum effective mass;

selecting the lower of the patient'"'"'s mass and maximum effective mass;

determining activity hours (AH) for the radiopharmaceutical or radiopharmaceutical analog with the following equation (Equation I);

$\begin{array}{cc}\mathrm{AH}=\frac{\mathrm{TBD}\times <br><br>\left(M<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{or}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{MEM}\right)}{\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]}<br><br><br><br>\mathrm{where}<br><br>\left[\begin{array}{ccc}\underset{\mathrm{elec}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{elect}}+\underset{\mathrm{phot}}{\sum <br><br>}& {\mathrm{\Delta <br><br>}}_{\mathrm{phot}}<br><br>\text{\hspace{1em}<br><br>}<br><br>{\mathrm{\varphi <br><br>}}_{\mathrm{phot}}^{\mathrm{TB}}\end{array}\right]& \left(\mathrm{Equation}<br><br>\text{\hspace{1em}<br><br>}<br><br>I\right)\end{array}$

in Equation I represents the sum of electron energy and photon energy deposited in the total body of the patient by the radiopharmaceutical or radiopharmaceutical analog, and said determining activity hours uses the lower of the patient'"'"'s mass (M) or maximum effective mass (MEM) and the desired total body dose (TBD);

determining residence time of said administered tracer dose of the radiopharmaceutical or the radiopharmaceutical analog in the whole body of the patient, the residence time being correlated to the clearance profile; and

establishing the patient-specific dose of the radiopharmaceutical for the patient by solving for therapeutic dose in the following equation;

$\mathrm{therapeutic}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}=\frac{\mathrm{Activity}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{Hours}}{\mathrm{Residence}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{time}}\times <br><br>\frac{\mathrm{desired}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{total}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{body}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}}{\mathrm{maximum}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{tolerated}<br><br>\text{\hspace{1em}<br><br>}<br><br>\mathrm{dose}}.$

21. A composition according to claim 20, wherein determining the activity hours via Equation I comprises obtaining activity hours from a table or database that has been prepared using Equation I.

22. A computer system for use in determining a desired dose of a radiopharmaceutical to be administered to a patient, comprising:

an input device adapted to receive (a) an input of at least one patient parameter, (b) an input of an initial activity count of a radiotracer, and (c) an input of at least one subsequent activity count of the radiotracer;

a central processing unit adapted to determine (a) an activity hour parameter from said input of said at least one patient parameter to provide a maximum tolerated dose of the radiopharmaceutical, (b) a residence time of the radiopharmaceutical from said inputs of said initial activity count and said at least one subsequent activity count, and (c) a patient-specific dose of the radiopharmaceutical from said residence time and activity hour parameter determinations; and

an output device adapted to provide an output of said patient-specific dose.

23. A computer system according to claim 22, wherein the at least one patient parameter includes patient mass, and wherein said central processing unit is adapted to determine said activity hour parameter from a lesser one of the patient mass and a maximum effective mass.

24. A computer system according to claim 23, wherein said central processor is adapted to determine the maximum effective mass from a table of maximum effective mass versus patient height.

25. A computer system according to claim 22, wherein said central processing unit is adapted to determine the residence time by fitting a curve to the initial activity count and the at least one subsequent activity count and solving the curve for the residence time.

26. A computer system according to claim 22, wherein said central processing unit uses a least squares fit numerical method to fit the curve.

27. A computer system according to claim 22, wherein said output device is adapted to generate a warning that an additional vendor-provided dose is required if said central processing unit determines that said patient-specific dose exceeds a vendor-provided dose.

28. A computer system according to claim 22, wherein said central processing unit is adapted to determine the maximum effective mass from a formula of maximum effective mass versus patient height.

29. A computer system according to claim 22, further comprising a database of activity hour parameters for particular maximum tolerated doses and particular patient parameters, wherein said central processing unit utilizes said database to determine the activity hour parameter.

30. A computer system according to claim 22, wherein said central processing unit is adapted to correct said inputs of said initial and subsequent activity counts to take into account background radiation.

31. A computer system according to claim 30, wherein said input device is adapted to receive a background radiation count and wherein said central processing unit corrects for background radiation by subtracting the background radiation count from a corresponding one of said initial and subsequent activity counts.

32. A computer system according to claim 31, wherein said input device is adapted to receive an input of a plurality of activity counts and an input of a plurality of related background radiation counts, and wherein said central processing unit is adapted to determine a plurality of intermediate corrected activity counts from the activity counts and the related background radiation counts and to determine a corrected activity count as a mean of the intermediate corrected activity counts.

33. A computer software program for use in determining a desired dose of a radiopharmaceutical to be administered to a patient, said program being adapted to (a) receive an input of at least one patient parameter, (b) determine an activity hour parameter from the at least one patient parameter to provide a maximum tolerated dose of the radiopharmaceutical, (c) receive an input of an initial activity count of a radiotracer, (d) receive an input of at least one subsequent activity count of the radiotracer (e) determine a residence time of the radiopharmaceutical from the initial activity count and the at least one subsequent activity counts, (f) determine a patient specific dose of the radiopharmaceutical from the projected residence time and the activity hour parameter, and (g) provide an output of the patient-specific dose.

34. A computer software program according to claim 33, wherein the at least one patient parameter includes the patient mass, and the computer software program determines the activity hour parameter from the lesser one of the patient mass and a maximum effective mass.

35. A computer software program according to claim 34, further comprising a database maximum effective mass versus patient height, wherein said program determines the maximum effective mass from said database.

36. A computer software program according to claim 33, further comprising a database of activity hour parameters for particular maximum tolerated doses and particular patient parameters, wherein said program determines the activity hour parameter from said database.

37. A computer software program according to claim 33, wherein said program is adapted to correct the inputs of the initial and subsequent activity counts by taking into account background radiation.

38. A computer software program according to claim 37, wherein said program is adapted to receive an input of a background radiation count and to subtract the background radiation count from one of the input initial and subsequent activity counts.