Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration

Abstract

The present invention relates to systems and methods for obtaining optimized EPO dosage regimens for a desired pharmacodynamic/pharmacokinetic response. The system includes choosing one or more EPO dosage regimens, then using a PK/PD model to determine the pharmacodynamic/pharmacokinetic profile of one or more EPO dosage regimens, and finally selecting one of the EPO dosage regimens for administration to achieve the desired pharmacodynamic/pharmacodynamic response based on the EPO profile.

1 - 203 . (canceled)  
   
   
       204 . A method comprising the steps of: 
 (a) choosing on or more EPO dosage regimens, wherein said one or more EPO dosage regimens maintains at least a serum EPO concentration above a predose level for about 5 to 30 days;    (b) using a pharmacokinetic/pharmacodynamic model to determine the pharmacodynamic profile of said one or more EPO dosage regimens; and    (c) selecting said one or more EPO dosage regimens that provide said desired pharmacodynamic response based on said pharmacodynamic profile.    
   
   
       205 . The method of  claim 204 , wherein said serum EPO concentration is sufficient to increase production of red blood cells.  
   
   
       206 . The method of  claim 205 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about a week.  
   
   
       207 . The method of  claim 205 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about two weeks.  
   
   
       208 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering EPO about once a week.  
   
   
       209 . The method of  claim 208 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 300 IU/kg to about 2400 IU/kg.  
   
   
       210 . The method of  claim 208 , wherein said once a week dosing regimen comprises administering a dose of EPO in the range of about 30,000 IU to about 54,000 IU.  
   
   
       211 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering a dose of EPO about once every two weeks.  
   
   
       212 . The method of  claim 211 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 900 IU/kg to about 1200 IU/kg.  
   
   
       213 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering EPO about once every ten days.  
   
   
       214 . The method of  claim 213 , wherein said every ten days EPO dosing regimen comprises administering a dose of EPO of about 900 IU/kg.  
   
   
       215 . The method of  claim 204 ,  206 ,  208 ,  211 , or  213 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of epoietin alpha and darbepoietin alpha.  
   
   
       216 . The method of  claim 204 ,  206 ,  208 ,  211 , or  213 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of novel erythropoiesis stimulating protein (NESP), human erythropoietin analog, erythropoietin receptor agonist, and erythropoietin omega.  
   
   
       217 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering proteins having EPO biological activity.  
   
   
       218 . The method of  claim 217 , wherein said proteins having EPO biological activity are selected from the group consisting of erythropoietin analogs, erythropoietin isoforms, and renal erythropoietin.  
   
   
       219 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of naturally occurring EPO, recombinant EPO, and synthetic EPO.  
   
   
       220 . The method of  claim 204 , wherein said patient has anemia.  
   
   
       221 . The method of  claim 220 , wherein said anemia comprises EPO concentration related anemia.  
   
   
       222 . The method of  claim 221 , wherein said anemia comprises end-stage renal or renal failure related anemia, and dialysis related anemia.  
   
   
       223 . The method of  claim 220 , wherein said anemia comprises cancer chemotherapy related anemia.  
   
   
       224 . The method of  claim 220 , wherein said anemia comprises AIDS drug therapy related anemia.  
   
   
       225 . The method of  claim 220 , wherein said anemia comprises drug related anemia.  
   
   
       226 . The method of  claim 225 , wherein said drug is selected from the group consisting of cisplatin and carboplatin.  
   
   
       227 . The method of  claim 225 , wherein said drug is zidovudine.  
   
   
       228 . The method of  claim 204 , is undergoing transfusion.  
   
   
       229 . The method of  claim 204 , wherein said patient is recovering from bone marrow transplant.  
   
   
       230 . The method of  claim 204 , wherein said patient has rheumatoid arthritis.  
   
   
       231 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering EPO via a route selected from the group consisting of intravenous administration, subcutaneous administration, and parenteral administration.  
   
   
       232 . The method of  claim 204 , wherein said EPO dosing regimen comprises administering EPO having a modified glycosylation pattern.  
   
   
       233 . The method of  claim 232 , wherein said EPO having a modified glycosylation pattern comprises darbepoietin alpha.  
   
   
       234 . A method comprising the steps of: 
 a) selecting one or more desired pharmacodynamic responses;    b) using a pharmacokinetic/pharmacodynamic model to determine EPO dosage regimens that provides said desired one or more pharmacodynamic responses; and    c) selecting the one or more EPO dosage regimens that provide said desired pharmacodynamic responses, wherein said one or more EPO dosage regimens maintains at least a serum EPO concentration above a predose level for about 5 to about 30 days.    
   
   
       235 . The method of  claim 234 , wherein said serum EPO concentration is sufficient to increase production of red blood cells.  
   
   
       236 . The method of  claim 235 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about a week.  
   
   
       237 . The method of  claim 235 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about two weeks.  
   
   
       238 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering EPO about once a week.  
   
   
       239 . The method of  claim 238 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 300 IU/kg to about 2400 IU/kg.  
   
   
       240 . The method of  claim 238 , wherein said once a week dosing regimen comprises administering a dose of EPO in the range of about 30,000 IU to about 54,000 IU.  
   
   
       241 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering a dose of EPO about once every two weeks.  
   
   
       242 . The method of  claim 241 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 900 IU/kg to about 1200 IU/kg.  
   
   
       243 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering EPO about once every ten days.  
   
   
       244 . The method of  claim 243 , wherein said every ten days EPO dosing regimen comprises administering a dose of EPO of about 900 IU/kg.  
   
   
       245 . The method of  claim 234 ,  236 ,  238 ,  241 , or  243 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of epoietin alpha and darbepoietin alpha.  
   
   
       246 . The method of  claim 234 ,  236 ,  238 ,  241 , or  243 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of novel erythropoiesis stimulating protein (NESP), human erythropoietin analog, erythropoietin receptor agonist, and erythropoietin omega.  
   
   
       247 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering proteins having EPO biological activity.  
   
   
       248 . The method of  claim 247 , wherein said proteins having EPO biological activity are selected from the group consisting of erythropoietin analogs, erythropoietin isoforms, and renal erythropoietin.  
   
   
       249 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of naturally occurring EPO, recombinant EPO, and synthetic EPO.  
   
   
       250 . The method of  claim 234 , wherein said patient has anemia.  
   
   
       251 . The method of  claim 250 , wherein said anemia comprises EPO concentration related anemia.  
   
   
       252 . The method of  claim 251 , wherein said anemia comprises end-stage renal or renal failure related anemia, and dialysis related anemia.  
   
   
       253 . The method of  claim 250 , wherein said anemia comprises cancer chemotherapy related anemia.  
   
   
       254 . The method of  claim 250 , wherein said anemia comprises AIDS drug therapy related anemia.  
   
   
       255 . The method of  claim 250 , wherein said anemia comprises drug related anemia.  
   
   
       256 . The method of  claim 255 , wherein said drug is selected from the group consisting of cisplatin and carboplatin.  
   
   
       257 . The method of  claim 255 , wherein said drug is zidovudine.  
   
   
       258 . The method of  claim 234 , is undergoing transfusion.  
   
   
       259 . The method of  claim 234 , wherein said patient is recovering from bone marrow transplant.  
   
   
       260 . The method of  claim 234 , wherein said patient has rheumatoid arthritis.  
   
   
       261 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering EPO via a route selected from the group consisting of intravenous administration, subcutaneous administration, and parenteral administration.  
   
   
       262 . The method of  claim 234 , wherein said EPO dosing regimen comprises administering EPO having a modified glycosylation pattern.  
   
   
       263 . The method of  claim 262 , wherein said EPO having a modified glycosylation pattern comprises darbepoietin alpha.  
   
   
       264 . A method comprising the steps of: 
 a) choosing on or more EPO dosage regimens, wherein said one or more EPO dosage regimens maintains at least a serum EPO concentration above a predose level for about 5 to 30 days;    b) using a pharmacokinetic/pharmacodynamic model to determine the pharmacokinetic profile of said one or more EPO dosage regimens; and    c) selecting said one or more EPO dosage regimens that provide said desired pharmacokinetic response based on said pharmacokinetic profile.    
   
   
       265 . The method of  claim 264 , wherein said serum EPO concentration is sufficient to increase production of red blood cells.  
   
   
       266 . The method of  claim 265 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about a week.  
   
   
       267 . The method of  claim 265 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about two weeks.  
   
   
       268 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering EPO about once a week.  
   
   
       269 . The method of  claim 268 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 300 IU/kg to about 2400 IU/kg.  
   
   
       270 . The method of  claim 268 , wherein said once a week dosing regimen comprises administering a dose of EPO in the range of about 30,000 IU to about 54,000 IU.  
   
   
       271 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering a dose of EPO about once every two weeks.  
   
   
       272 . The method of  claim 271 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 900 IU/kg to about 1200 IU/kg.  
   
   
       273 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering EPO about once every ten days.  
   
   
       274 . The method of  claim 273 , wherein said every ten days EPO dosing regimen comprises administering a dose of EPO of about 900 IU/kg.  
   
   
       275 . The method of  claim 264 ,  266 ,  267 ,  268 ,  271 , or  273 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of epoietin alpha and darbepoietin alpha.  
   
   
       276 . The method of  claim 264 ,  266 ,  268 ,  271 , or  273 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of novel erythropoiesis stimulating protein (NESP), human erythropoietin analog, erythropoietin receptor agonist, and erythropoietin omega.  
   
   
       277 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering proteins having EPO biological activity.  
   
   
       278 . The method of  claim 277 , wherein said proteins having EPO biological activity are selected from the group consisting of erythropoietin analogs, erythropoietin isoforms, and renal erythropoietin.  
   
   
       279 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of naturally occurring EPO, recombinant EPO, and synthetic EPO.  
   
   
       280 . The method of  claim 264 , wherein said patient has anemia.  
   
   
       281 . The method of  claim 280 , wherein said anemia comprises EPO concentration related anemia.  
   
   
       282 . The method of  claim 281 , wherein said anemia comprises end-stage renal or renal failure related anemia, and dialysis related anemia.  
   
   
       283 . The method of  claim 280 , wherein said anemia comprises cancer chemotherapy related anemia.  
   
   
       284 . The method of  claim 280 , wherein said anemia comprises AIDS drug therapy related anemia.  
   
   
       285 . The method of  claim 280 , wherein said anemia comprises drug related anemia.  
   
   
       286 . The method of  claim 285 , wherein said drug is selected from the group consisting of cisplatin and carboplatin.  
   
   
       287 . The method of  claim 285 , wherein said drug is zidovudine.  
   
   
       288 . The method of  claim 264 , is undergoing transfusion.  
   
   
       289 . The method of  claim 264 , wherein said patient is recovering from bone marrow transplant.  
   
   
       290 . The method of  claim 264 , wherein said patient has rheumatoid arthritis.  
   
   
       291 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering EPO via a route selected from the group consisting of intravenous administration, subcutaneous administration, and parenteral administration.  
   
   
       292 . The method of  claim 264 , wherein said EPO dosing regimen comprises administering EPO having a modified glycosylation pattern.  
   
   
       293 . The method of  claim 292 , wherein said EPO having a modified glycosylation pattern comprises darbepoietin alpha.  
   
   
       294 . A method comprising the steps of 
 a) selecting one or more desired pharmacokinetic responses;    b) using a pharmacokinetic/pharmacodynamic model to determine EPO dosage regimens that provide said desired one or more pharmacokinetic responses, and    c) selecting one or more EPO dosage regimens that provide said desired pharmacokinetic responses, wherein said one or more EPO dosage regimens maintains at least a serum EPO concentration above a predose level for about 5 to 30 days.    
   
   
       295 . The method of  claim 294 , wherein said serum EPO concentration is sufficient to increase production of red blood cells.  
   
   
       296 . The method of  claim 295 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about a week.  
   
   
       297 . The method of  claim 295 , wherein said serum EPO concentration is sufficient to maintain increased red blood cell production for at least about two weeks.  
   
   
       298 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering EPO about once a week.  
   
   
       299 . The method of  claim 298 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 300 IU/kg to about 2400 IU/kg.  
   
   
       300 . The method of  claim 298 , wherein said once a week dosing regimen comprises administering a dose of EPO in the range of about 30,000 IU to about 54,000 IU.  
   
   
       301 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering a dose of EPO about once every two weeks.  
   
   
       302 . The method of  claim 301 , wherein said once a week EPO dosing regimen comprises administering a dose of EPO in the range of about 900 IU/kg to about 1200 IU/kg.  
   
   
       303 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering EPO about once every ten days.  
   
   
       304 . The method of  claim 303 , wherein said every ten days EPO dosing regimen comprises administering a dose of EPO of about 900 IU/kg.  
   
   
       305 . The method of  claim 294 ,  296 ,  297 ,  298 ,  301 , or  303 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of epoietin alpha and darbepoietin alpha.  
   
   
       306 . The method of  claim 294 ,  296 ,  297 ,  298 ,  301 , or  303 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of novel erythropoiesis stimulating protein (NESP), human erythropoietin analog, erythropoietin receptor agonist, and erythropoietin omega.  
   
   
       307 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering proteins having EPO biological activity.  
   
   
       308 . The method of  claim 307 , wherein said proteins having EPO biological activity are selected from the group consisting of erythropoietin analogs, erythropoietin isoforms, and renal erythropoietin.  
   
   
       309 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering EPO selected from the group consisting of naturally occurring EPO, recombinant EPO, and synthetic EPO.  
   
   
       310 . The method of  claim 294 , wherein said patient has anemia.  
   
   
       311 . The method of  claim 310 , wherein said anemia comprises EPO concentration related anemia.  
   
   
       312 . The method of  claim 311 , wherein said anemia comprises end-stage renal or renal failure related anemia, and dialysis related anemia.  
   
   
       313 . The method of  claim 310 , wherein said anemia comprises cancer chemotherapy related anemia.  
   
   
       314 . The method of  claim 310 , wherein said anemia comprises AIDS drug therapy related anemia.  
   
   
       315 . The method of  claim 310 , wherein said anemia comprises drug related anemia.  
   
   
       316 . The method of  claim 315 , wherein said drug is selected from the group consisting of cisplatin and carboplatin.  
   
   
       317 . The method of  claim 315 , wherein said drug is zidovudine.  
   
   
       318 . The method of  claim 294 , is undergoing transfusion.  
   
   
       319 . The method of  claim 294 , wherein said patient is recovering from bone marrow transplant.  
   
   
       320 . The method of  claim 294 , wherein said patient has rheumatoid arthritis.  
   
   
       321 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering EPO via a route selected from the group consisting of intravenous administration, subcutaneous administration, and parenteral administration.  
   
   
       322 . The method of  claim 294 , wherein said EPO dosing regimen comprises administering EPO having a modified glycosylation pattern.  
   
   
       323 . The method of  claim 232 , wherein said EPO having a modified glycosylation pattern comprises darbepoietin alpha.