We claim:
1. A method for processing a telephone call from a wireless subscriber unit that is part of a wireless telephone system, comprising:
(a) receiving a request to make said telephone call to a receiving subscriber unit;
(b) devocoding vocoded data from said wireless subscriber unit if said receiving subscriber unit is a wire-based subscriber unit; and
(c) delivering said vocoded data to said receiving subscriber unit if said receiving subscriber unit is a wireless subscriber unit.
2. The method as set forth in claim 1 wherein said delivering includes:
(c.1) routing said vocoded data to said receiving subscriber unit within said wireless telephone system if said receiving subscriber unit is part of said wireless telephone system; and
(c.2) routing said vocoded data through a long distance telecommunications system if said receiving subscriber unit is part of a second wireless telephone system.
3. The method as set forth in claim 2 wherein said routing said vocoded data through a long distance telecommunications system includes:
establishing an all-digital link to said second wireless telephone system; and
delivering said vocoded data to said second wireless system over said all-digital link.
4. The method as set forth in claim 3 wherein said all-digital link is an ATM network.
5. The method as set forth in claim 3 wherein said all-digital link passes through a local public switched telephone network and a long distance telecommunications system.
6. The method as set forth in claim 1 further comprising:
receiving a conference call request from said wireless subscriber unit directed to a third subscriber unit;
converting said vocoded data from said wireless subscriber unit into combinable data;
generating combined data by combining said combinable data and data from said third subscriber unit; and
generating combined vocoded data by vocoding said combined data and transmitting said combined vocoded data to said receiving subscriber unit.
7. The method as set forth in claim 6 wherein said combinable data is pulse code modulated data.
8. The method as set forth in claim 1 further comprising:
detecting an incoming call to said wireless subscriber unit from a third subscriber unit;
allocating signal processing resources to place data from said third subscriber unit into vocoded format if said third subscriber unit is part of another telephone system; and
transmitting said data from said third subscriber unit to said wireless subscriber unit when call waiting is activated.
9. A cellular telephone system for processing a telephone call from a requesting subscriber unit that is part of a wireless telephone system directed to a receiving subscriber unit comprising:
signal routing circuitry;
signal processing circuitry for processing vocoded data; and
a call control processor, coupled to said signal processing circuitry and said signal routing circuitry, for configuring said signal routing circuitry to bypass said signal processing circuitry if said receiving subscriber unit is part of said cellular telephone system, and for configuring said signal processing circuitry to devocode said vocoded data if said receiving subscriber unit is wire-based.
10. The cellular telephone system as set forth in claim 9 wherein said call control processor requests an all-digital connection to said receiving subscriber unit if said receiving subscriber unit is part of a second wireless telephone system, and configures said signal routing circuitry to deliver said vocoded data to said receiving subscriber unit through said all-digital connection.
11. The cellular telephone system as set forth in claim 10 wherein said all-digital connection passes through a local public switched telephone network and a long distance telecommunications system.
12. The cellular telephone system as set forth in claim 10 wherein said all-digital connection is an asynchronous transfer mode network.
13. The cellular telephone system as set forth in claim 9 wherein said signal routing circuitry further comprises an interconnect subsystem.
14. The cellular telephone system as set forth in claim 9 wherein said call control processor configures said signal processing circuitry to convert said vocoded data into tones if said receiving subscriber unit is part of a second wireless telephone system, and configures said signal routing circuitry to deliver said tones to a long distance telecommunications carrier.
15. The cellular telephone system as set forth in claim 9 wherein:
said call control processor receives a conference call request from said wireless subscriber unit directed to a third subscriber unit, and configures said signal processing circuitry to convert said vocoded data from said wireless subscriber unit into combinable data, to generate combined data by combining said combinable data and data from said third subscriber unit, and to generate combined vocoded data by vocoding said combined data and transmitting said combined vocoded data to said receiving subscriber unit.
16. The cellular telephone systems as set forth in claim 15 wherein said combinable data is pulse code modulated data.
17. The cellular telephone system as set forth in claim 9 wherein:
said call control processor detects an incoming call to said wireless subscriber unit from a third subscriber unit and configures said signal processing resources to place data from said third subscriber unit into vocoded format if said third subscriber unit is part of another telephone system if call waiting is activated.
18. A wireless telephone system for processing a telephone call from a requesting subscriber unit that is part of a wireless telephone system directed to a receiving subscriber unit comprising:
means for routing digital information;
means for processing vocoded data; and
means for configuring said means for routing to bypass said means for processing if said receiving subscriber unit is part of said wireless telephone system, and for configuring said means for processing to devocode said vocoded data if said receiving subscriber unit is wire based, said means for configuring being coupled to said means for processing and said means for routing.
19. The wireless telephone system of claims 18 wherein said means for configuring configures said means for routing to route said vocoded data to said receiving subscriber unit within said wireless telephone system if said receiving subscriber unit is part of said wireless subscriber system, and to route said vocoded data through a long distance telecommunication service if said receiving subscriber unit is part of a second wireless telephone system.
20. The wireless telephone system as set forth in claim 19 wherein said means for routing comprises an interconnect subsystem;
21. The wireless telephone system as set forth in claim 20 wherein said means for configuring configures said means for processing to convert said vocoded data into tones, and configures said means for routing to deliver said signal to a long distance telecommunications carrier, if said receiving subscriber unit is part of a second wireless telephone system.
22. The wireless telephone system as set forth in claim 21 wherein said means for configuring requests an all-digital connection to said receiving subscriber unit if said receiving subscriber unit is part of a second wireless telephone system, and configures said means for routing to deliver said vocoded data to said receiving subscriber unit through said all-digital connection if said al digital connection is supplied.
23. The wireless telephone system as set forth in claim 22 wherein said all-digital connection passes through a local public switched telephone network and a long distance telecommunications system.
24. The wireless telephone system as set forth in claim 23 wherein said all-digital connection is an asynchronous transfer mode network.
25. The wireless telephone system as set forth in claim 18 wherein:
said means for controlling receives a conference call request from said wireless subscriber unit directed to a third subscriber unit, and configures said means for processing to convert said vocoded data from said wireless subscriber unit into combinable data, to generate combined data by combining said combinable data and data from said third subscriber unit, and to generate combined vocoded data by vocoding said combined data and transmitting said combined vocoded data to said receiving subscriber unit.
26. The wireless telephone systems as set forth in claim 25 wherein said combinable data is pulse code modulated data.
27. The wireless telephone system as set forth in claim 18 wherein:
said means for configuring detects an incoming call to said wireless subscriber unit from a third subscriber unit and configures said means for processing to place data from said third subscriber unit into vocoded format if said third subscriber unit is part of another telephone system.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of determining bioequivalence between a reference brand-name drug and a generic drug product for administering to a subject, the method comprising:
a. determining pharmacokinetic parameters of the reference brand-name drug and the generic drug product
b. determining toxicity associated with administration of the reference brand-name drug and the generic drug product
c. comparing the pharmacokinetic parameters and the toxicity profiles of the reference brand-name drug and the generic drug product
wherein equivalent pharmacokinetic parameters combined with equivalent toxicity profiles of the reference brand-name drug and the generic drug product indicate bioequivalence of the reference brand-name drug and the generic drug product when administered to the subject.
2. The method of claim 1, wherein the generic drug is a pegylated liposomal doxorubicin (PLD).
3. The method of claim 1, wherein the reference brand-name drug is Doxorubicin HCl Liposome Injection (Doxil).
4. The method of claim 1, wherein the toxicity is skin toxicity.
5. The method of claim 1, wherein the toxicity is palmar plantar erythrodysesthesia (PPE).
6. The method of claim 1, wherein the toxicity profile is PPE severity grade, dose reduction or delays caused by PPE.
7. The method of claim 5 or 6, wherein PPE serves as an in-vivo bioassay indicative of tissue bioavailability of the generic drug product and the reference brand-name drug.
8. The method of claim 1, wherein the pharmacokinetic parameter is selected from the group consisting of absorption rate constant, bioavailability, apparent volume of distribution, steady-state volume of distribution, unbound fraction, rate of elimination, clearance, renal clearance, metabolic clearance, fraction excreted unchanged, elimination rate constant, biologic half-life, maximum concentration, and area under the concentration vs. time curve (AUC).
9. The method of claim 1, wherein levels of total doxorubicin and its metabolite, doxorubicinol in plasma and urine are measured.
10. A method of claim 9, wherein the levels of liposome-associated and free doxorubicin in plasma are measured.
11. A method of claim 10, wherein the proportion of liposome associated to free doxorubicin in plasma is an indication of bioavailability of doxorubicin in plasma.
12. A method of claim 11, wherein a high proportion of liposome-associated doxorubicin is an indication of lack of bioavailability in plasma.
13. The method of claim 1, wherein the pharmacokinetic parameter is a delay in the appearance of doxorubicinol in plasma.
14. A method of claim 13, wherein equivalent delay in the appearance of doxorubicinol in plasma of the drug product relative to the reference brand-name drug combined with equivalent AUC of doxorubicinol in plasma of the drug product relative to the reference brand-name drug indicate equivalent tissue bioavailability of the generic drug product relative to the reference brand-name drug.
15. A method of claims 8 and 14, wherein equivalent PK parameters and tissue bioavailability of the drug product relative to the reference brand-name drug indicate bioequivalence between the drug product and the reference brand-name drug.
16. The method of claim 1, wherein the bioequivalence is met if the 90% confidence interval (CI) of the mean Cmax, AUC(0-t) and AUC(0-\u221e) of the generic drug product relative to the reference brand-name drug is within 80% to 125%.
17. The method of claim 1, wherein the bioequivalence determined meets the requirements set by the FDA.
18. The method of claim 1, wherein the subject is a mammal.
19. The method of claim 1, wherein the subject is a human.
20. The method of claim 1, wherein the method is used to identify a generic drug product having an effective bioequivalence to the reference brand-name drug for administering to a subject.
21. The method of claim 1, wherein the method is used to identify generic PLD products having an effective bioequivalence to doxorubicin hydrochloric acid liposome injection (Doxil) for administering to a subject.
22. A method of assessing bioequivalence between a generic pegylated liposomal doxorubicin (PLD) product and a reference doxorubicin hydrochloric acid liposome injection (Doxil) for administering to a subject, the method comprising:
a. determining pharmacokinetic parameters of doxorubicin hydrochloric acid liposome injection (Doxil) and the generic PLD product
b. determining toxicity associated with administration of doxorubicin hydrochloric acid liposome injection (Doxil) and the generic PLD product
c. comparing the pharmacokinetic parameters and the toxicity profiles of doxorubicin hydrochloric acid liposome injection (Doxil) and the generic PLD product
wherein equivalent pharmacokinetic parameters plus equivalent toxicity profiles of Doxil and the generic PLD product indicate bioequivalence of Doxil and the generic PLD product when administered to the subject.
23. The method of claim 22, wherein the toxicity is skin toxicity.
24. The method of claim 22, wherein the toxicity is palmar plantar erythrodysesthesia (PPE).
25. The method of claim 22, wherein the toxicity profile is PPE toxicity grade or dose modifications.
26. The method of claim 24 or 25, wherein PPE is indicative of tissue bioavailability of the generic PLD product and Doxil.
27. The method of claim 22, wherein the pharmacokinetic parameter is selected from the group consisting of absorption rate constant, bioavailability, apparent volume of distribution, steady-state volume of distribution, unbound fraction, rate of elimination, clearance, renal clearance, metabolic clearance, fraction excreted unchanged, elimination rate constant, biologic half-life, maximum concentration, and Area under Curve.
28. The method of claim 22, wherein levels of doxorubicin and its metabolite, doxorubicinol in plasma and urine are measured.
29. The method of claim 22, wherein the pharmacokinetic parameter is a delay in the appearance of doxorubicinol in plasma.
30. The method of claim 22, wherein the bioequivalence is met if the 90% confidence interval (CI) of the mean Cmax, AUC(0-t) and AUC(0-\u221e) of the generic drug product relative to the reference brand-name drug is within 80% to 125%.
31. The method of claim 22, wherein the bioequivalence determined meets the requirements set by the FDA.
32. The method of claim 22, wherein the subject is a mammal.
33. The method of claim 22, wherein the subject is a human.
34. The method of claim 22, wherein the method is used to identify generic PLD products having an effective bioequivalence to doxorubicin hydrochloric acid liposome injection (Doxil) for administering to a subject.
35. A kit for determining bioequivalence between doxorubicin hydrochloric acid liposome injection (Doxil) and a generic PLD product, the kit comprising:
a. a generic PLD product
b. reagents for performing in vitro and in vivo pharmacokinetic assays
c. instructions for using the kit
36. The kit of claim 35 further comprising more than one generic PLD product.
37. The kit of claim 35 further comprising an instrument for performing in vivo pharmacokinetic study.
38. The kit of claim 35 further comprising a computer readable program or software for performing pharmacokinetic andor statistical analysis.
39. A method of determining bioequivalence between an FDA-approved reference drug product and a pharmaceutically equivalent product that is produced using a manufacturing change relative to the reference product, the method comprising:
a. determining pharmacokinetic parameters of the reference drug and the pharmaceutically equivalent product
b. determining toxicity associated with administration of the reference drug and the pharmaceutically equivalent product
c. comparing the pharmacokinetic parameters and the toxicity profiles of the reference drug and the pharmaceutically equivalent product
wherein equivalent pharmacokinetic parameters combined with equivalent toxicity profiles of the reference drug and a pharmaceutically equivalent product indicate bioequivalence of the reference drug with the pharmaceutically equivalent product made with a manufacturing change.
40. The method of claim 39, wherein the manufacturing change is a new manufacturing site andor equipment.
41. The method of claim 39, wherein the manufacturing change is an alternative process or process step.
42. The method of claim 39, wherein the manufacturing change is a new source of raw materials.
43. The method of claim 39, wherein the pharmaceutically equivalent drug is a pegylated liposomal doxorubicin (PLD).
44. The method of claim 39, wherein the reference drug is Doxorubicin HCl Liposome Injection (Doxil).
45. The method of claim 39, wherein the toxicity is skin toxicity.
46. The method of claim 39, wherein the toxicity is palmar plantar erythrodysesthesia (PPE).
47. The method of claim 39, wherein the toxicity profile is PPE toxicity grade or dose modifications.
48. The method of claim 46 or 47, wherein PPE is indicative of tissue bioavailability of the pharmaceutically equivalent product and the reference drug.
49. The method of claim 39, wherein the pharmacokinetic parameter is selected from the group consisting of absorption rate constant, bioavailability, apparent volume of distribution, steady-state volume of distribution, unbound fraction, rate of elimination, clearance, renal clearance, metabolic clearance, fraction excreted unchanged, elimination rate constant, biologic half-life, maximum concentration, and area under the concentration vs. time curve (AUC).
50. The method of claim 39, wherein levels of doxorubicin and its metabolite, doxorubicinol in plasma and urine are measured.
51. The method of claim 39, wherein the pharmacokinetic parameter is a delay in the appearance of doxorubicinol in plasma.
52. The method of claim 39, wherein the bioequivalence is met if 90% confidence interval (CI) of the mean Cmax, AUC(0-t) and AUC(0-\u221e) of the pharmaceutically equivalent drug product relative to the reference drug is within 80% to 125%.
53. The method of claim 39, wherein the bioequivalence determined meets the requirements set by the FDA.