CKD-391 DDI : Atorvastatin and Ezetimibe in Healthy Volunteers

Study Overview
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Brief Summary
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A randomized open-label, multiple dose, three-treatment, three-period, six-sequence, crossover study to investigate the pharmacokinetic drug interaction between Atorvastatin and Ezetimibe after oral administration in healthy volunteers

Detailed Description
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Outcome Measures Primary endpoint AUCτ,ss, Cmax,ss of atorvastatin and free ezetimibe Second endpoint 1) AUCinf,ss, Cavg,ss, %fluctuation, tmax,ss, t1/2, CL/Fss, Vd/Fss of atorvastatin and free ezetimibe 2) AUCτ,ss, AUCinf,ss, Cmax,ss, tmax,ss, t1/2, metabolic ratio of 2-hydroxy atorvastatin and free ezetimibe

Official Title
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CKD-391 in Healthy Volunteers to Investigate the Pharmacokinetic Drug Interaction Between Atorvastatin an Ezetimibe After Oral Administration

Conditions
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Healthy

Intervention / Treatment
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* Drug: 1 (Lipitor®)
* Drug: 1 (Ezetrol®)
* Drug: 1 (Lipitor®, Ezetrol®)
* Drug: 2 (Ezetrol®)
* Drug: 2(Lipitor®, Ezetrol®)
* Drug: 2 (Lipitor®)
* Drug: 3(Lipitor®, Ezetrol®)
* Drug: 3 (Lipitor®)
* Drug: 3 (Ezetrol®)
* Drug: 4 (Lipitor®)
* Drug: 4(Lipitor®, Ezetrol®)
* Drug: 4 (Ezetrol®)
* Drug: 5 (Ezetrol®)
* Drug: 5 (Lipitor®)
* Drug: 5 (Lipitor®, Ezetrol®)
* Drug: 6(Lipitor®, Ezetrol®)
* Drug: 6 (Ezetrol®)
* Drug: 6 (Lipitor®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age Eligible for Study : 19 Years to 45 Years If males, Body weight ≥ 55kg, If females, Body weight ≥ 50kg BSA ≥ 18.5, <25 Accepts healthy volunteers If female, Negative for pregnancy test at the screening and pre dose of Day 1 The subjects who agree with performing contraception during the study The subjects who agreed with written informed consent Exclusion Criteria: The subjects with impaired hepatic function, renal function, nervous system etc. The subjects have a gastrointestinal disease or surgery which can be effected in absorption of Investigational product The subjects with high blood pressure or low blood pressure (Systolic blood pressure>150mmHg or <90mmHg, Diastolic blood pressure>100mmHg or <50mmHg The subjects with abnormal Laboratory test (AST, ALT>1.25 fold of upper normal limit, Total bilirubin>1.5 fold of upper normal limit, CPK>2 fold of upper normal limit, Estimated Glomerular filtration rate<60mL/min/1.73m2 by Modification of Diet in Renal disease formula The subjects have drug abuse history within 1year or Positive for urine drug test at screening The subjects who took prescription only medicine whch can be effected in metabolism of Investigational product within 14days The subjects who took over the counter drug whch can be effected in metabolism of Investigational product within 7days

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1(Lipitor®>Ezetrol®>Lipitor®, Ezetrol®)<br>Three treatment atorvastatin calcium 40mg will be administration to healthy volunteers during 7days after 11days withdrawal period, ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days | Drug: 1 (Lipitor®)<br>* atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;Drug: 1 (Ezetrol®)<br>* After 11days withdrawal period, ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;Drug: 1 (Lipitor®, Ezetrol®)<br>* After 11days withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;|
| Experimental: 2(Ezetrol®>Lipitor®, Ezetrol®>Lipitor®)<br>Three treatment ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg will be administered to healthy volunteers during 7days | Drug: 2 (Ezetrol®)<br>* ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;Drug: 2(Lipitor®, Ezetrol®)<br>* After 11days withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;Drug: 2 (Lipitor®)<br>* After 11day withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;|
| Experimental: 3(Lipitor®, Ezetrol®>Lipitor®>Ezetrol®)<br>Three treatment atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg will be administered to healthy volunteers during 7days after 11days withdrawal period, ezetimibe 10mg will be administered to healthy volunteers during 7days | Drug: 3(Lipitor®, Ezetrol®)<br>* atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;Drug: 3 (Lipitor®)<br>* After 11day withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;Drug: 3 (Ezetrol®)<br>* After 11day withdrawal period, ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;|
| Experimental: 4(Lipitor®>Lipitor®, Ezetrol®>Ezetrol®)<br>atorvastatin calcium 40mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, ezetimibe 10mg will be administered to healthy volunteers during 7days | Drug: 4 (Lipitor®)<br>* atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;Drug: 4(Lipitor®, Ezetrol®)<br>* After 11days withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;Drug: 4 (Ezetrol®)<br>* After 11day withdrawal period, ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;|
| Experimental: 5(Ezetrol®>Lipitor®>Lipitor®, Ezetrol®)<br>ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days | Drug: 5 (Ezetrol®)<br>* ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;Drug: 5 (Lipitor®)<br>* After 11day withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;Drug: 5 (Lipitor®, Ezetrol®)<br>* After 11days withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;|
| Experimental: 6(Lipitor®, Ezetrol®>Ezetrol®>Lipitor®)<br>atorvastatin calcium 40mg and ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, ezetimibe 10mg will be administered to healthy volunteers during 7days after 11days withdrawal period, atorvastatin calcium 40mg will be administered to healthy volunteers during 7days | Drug: 6(Lipitor®, Ezetrol®)<br>* atorvastatin calcium 40mg, Lipitor® 40mg and ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg, Ezetrol® 10mg;Drug: 6 (Ezetrol®)<br>* After 11days withdrawal period, ezetimibe 10mg, Ezetrol® 10mg will be administered to healthy volunteers during 7days<br>* Other names: Ezetrol® 10mg;Drug: 6 (Lipitor®)<br>* After 11day withdrawal period, atorvastatin calcium 40mg, Lipitor® 40mg will be administered to healthy volunteers during 7days<br>* Other names: Lipitor® 40mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCτ,ss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| Cmax,ss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCinf,ss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| Cavg,ss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| %fluctuation of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| tmax,ss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| t1/2 of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| CL/Fss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| Vd/Fss of atorvastatin and free ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| AUCτ,ss of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| AUCinf,ss of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| Cmax,ss of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| tmax,ss of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| t1/2 of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) | 
| metabolic ratio of 2-hydroxy atorvastatin and total ezetimibe | Atorvastatin single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h Ezetimibe single : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h Atorvastatin+Ezetimibe : just before the IP administration of D7(D24, D41) and after the IP administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96 h | common : just before the IP administration of D5(D22, D39), D6(D23, D40) |