Please answer it ... Your company want to develop a sustained release oral formulation of an already marketed API. The t
Posted: Mon Apr 04, 2022 6:41 am
Please answer it ...
Your company want to develop a sustained release oral
formulation of an already marketed API. The table below report data
for an iv-bolus administration, an oral solution of the API, the
already marketed tablet and two candidate new formulations
administered to the same subject (BGS, 33 years old, 78 kg).
Table 1 – Data provided
Iv-bolus
Oral solution
Marketed tablet
Sustained-release Tablet A
Sustained-release Tablet B
Dose (mg)
100
200
300
300
300
AUC (mg/L/hr)
365
625
855
893
932
AUMC (mg/L/hr2)
3160.173
5687.5
8379
8947.86
10438.4
From the data provided in Table 1, calculate the following:
Units
Iv-bolus
Oral solution
Marketed tablet
Sustained-release
Tablet A
Sustained-release Tablet B
Absolute F
Relative F (to oral solution)
MRT
MAT
MDT
Half-life
ka
Based on your calculations, what formulation (Tablet A or Tablet
B) appears more promising as a sustained release product?
Write a short report according to the provided guidelines.
Mean Residence Time Development Basic Principles of NCA Mean Residence Time (MRT) • Developed at the end of 70 • Very popular in the 80 . Now, less popular, however • Some basic MRT concepts are routinely dedin • Individual molecules cannot be counted, of course, but groups of them can • Letting n be the number of molecules remaining in the body for a time oft, and be the number remaining for time t, then the mean time of the two groups becomes WA+U extending this concept to account for all molecules administered, the MRT becomes MT Mean Residence Time Concept MRT estimation It can be demonstrated [1] that when clearance is constant with time MUT • A dose of drug comprises many millions of molecules . On administration, these drug molecules each spend a different time within the body. Some are eliminated rapidly, others stay for a long time. A few may remain for a lifetime • The result is a distribution of residence times that can be characterized by a mean value The mean residence time (MRT) is the average time the molecules introduced reside within the body, whether of the MRT mutation the bo Where the produits called the first moment of the concentration because concentration is multiplied by time raised to the power of 1 Therefore, the numerator is called the area under the first moment versus time curve (AUMCI, whereas the denominator is the area under the plava concentration-time curve (MUC) www
Graphical representation of AUC and AUMC What are the major use of MRT? • Example of the time course of both the plauna concentration and its first moment • Calculation of Vis • Absorption kinetic MRT: Working Definition With slow distribution V changes with time The mean residence time of a drug molecule in the body is defined as the ratio between the area under the first moment curve (AUMC) and the area under the concentration curve VERVIV Volume 14 OD AUC . Note that MRT cakulations require simple math skills V Time out 11
Calculation of Vss MRTs and Absorption kinetics • Methods so far: . If lv-infusion available: Vss = AR G C • MRT includes all the body but excludes those molecules that are never been absorbed . When MRT is estimated after an administration, it becomes MRT, because represents the real mean residence time in the body • MRT, excludes the molecules present at the absorption site • MRT = 1/2 where is the elimination rate constant Otherwise V V Thus strongly rely on the availability of good estimate of kand ka! Vss from MRT concept What about after an oral administration? • It can be demonstrated that V.CE- MRT This relationships makes the estimation Vss model independent • MRT after an oral administration will be the sum of the mean residence time in the body and the mean residence time at the absorption site (MAT) MRT MAT + MRT • Then MAT can be estimated by simple difference, if MRT is known from a previous bolus administration MAT = MRT - MRT • MAT is a robust and easy to estimate parameter • MAT Is a measure of absorption rate: 1/MAT • MAT can be used to compare absorption rate across several formulations 12 13
Mean Dissolution Time (MDT) Disadvantage • The mean dissolution time (MDT) is the time required for a drug molecule administered as a solid to dissolve at the absorption site • MAT can be partitioned into MOT and the mean time for absorption of dissolved drug (dd) (MAT MAT = MOT + MAT • Since an orally administered aqueous solution of drug does not require in vivo dissolution, it follows that the MAT resulting from such a solution equals MDL Then MOT - MATMAT • This is one of the simplest methods to estimate in vivo dissolution • AUMC estimation may not be accurate • Why? low concentration dat when the perimentare by targetime values so they have a big pictorial UMC • This amplifies the experimental error in the computation of AUMC Example Drug Xised to ne samo su ndio si BBC Summary MRT • MRT can be applied to a variety of problems in PK/PO... MRT at the effectie • MRT above the MC Their implementation it straightforward • MRT require cely the calculation of AC and ALMC • Numerical fitting is not required • Any tyre of concentration time profile can be analved with this method • The results are robust and reproducible 20 1ST w Estimate RT for each annan 2. Catinale for new MOT 15
Estimate MRT for each administration Estimate MDT MRT 997 43 233 Dissolution of the tablet MD.-MRT MRT. MRT 45 981 5082 MRZ = 6.0 MDT 60-45-15 848 Estimate MAT for the oral solution and the oral tablet Example 2 MAT - MRT MRT The MOT is estimated for three different oral formulations of drug X a, b, and the • MOT 0.53, MOT = 171, MOT, = 2.03 • Which has the longer in Wivo Giolition time? MAT =4.5-4.3 0.2
The Main Non-compartmental Parameters 22 Vz 11/22 CL = F.Dose F.Dose AUMC VSS = AUC2 AUC AUMC MRT = AUC Vss = CL. MRT MRT) = 1/k MAT = 1/kg Conclusions • NCA is a method to obtain basic PK parameters using a simpler mathematical approach compared to the compartmental models Rate Tmak, K, MAT Absorption Distribution Elimination first order) Extent 5. AUC Cmax V Vss, V2 FxDose 18
Your company want to develop a sustained release oral
formulation of an already marketed API. The table below report data
for an iv-bolus administration, an oral solution of the API, the
already marketed tablet and two candidate new formulations
administered to the same subject (BGS, 33 years old, 78 kg).
Table 1 – Data provided
Iv-bolus
Oral solution
Marketed tablet
Sustained-release Tablet A
Sustained-release Tablet B
Dose (mg)
100
200
300
300
300
AUC (mg/L/hr)
365
625
855
893
932
AUMC (mg/L/hr2)
3160.173
5687.5
8379
8947.86
10438.4
From the data provided in Table 1, calculate the following:
Units
Iv-bolus
Oral solution
Marketed tablet
Sustained-release
Tablet A
Sustained-release Tablet B
Absolute F
Relative F (to oral solution)
MRT
MAT
MDT
Half-life
ka
Based on your calculations, what formulation (Tablet A or Tablet
B) appears more promising as a sustained release product?
Write a short report according to the provided guidelines.
Mean Residence Time Development Basic Principles of NCA Mean Residence Time (MRT) • Developed at the end of 70 • Very popular in the 80 . Now, less popular, however • Some basic MRT concepts are routinely dedin • Individual molecules cannot be counted, of course, but groups of them can • Letting n be the number of molecules remaining in the body for a time oft, and be the number remaining for time t, then the mean time of the two groups becomes WA+U extending this concept to account for all molecules administered, the MRT becomes MT Mean Residence Time Concept MRT estimation It can be demonstrated [1] that when clearance is constant with time MUT • A dose of drug comprises many millions of molecules . On administration, these drug molecules each spend a different time within the body. Some are eliminated rapidly, others stay for a long time. A few may remain for a lifetime • The result is a distribution of residence times that can be characterized by a mean value The mean residence time (MRT) is the average time the molecules introduced reside within the body, whether of the MRT mutation the bo Where the produits called the first moment of the concentration because concentration is multiplied by time raised to the power of 1 Therefore, the numerator is called the area under the first moment versus time curve (AUMCI, whereas the denominator is the area under the plava concentration-time curve (MUC) www
Graphical representation of AUC and AUMC What are the major use of MRT? • Example of the time course of both the plauna concentration and its first moment • Calculation of Vis • Absorption kinetic MRT: Working Definition With slow distribution V changes with time The mean residence time of a drug molecule in the body is defined as the ratio between the area under the first moment curve (AUMC) and the area under the concentration curve VERVIV Volume 14 OD AUC . Note that MRT cakulations require simple math skills V Time out 11
Calculation of Vss MRTs and Absorption kinetics • Methods so far: . If lv-infusion available: Vss = AR G C • MRT includes all the body but excludes those molecules that are never been absorbed . When MRT is estimated after an administration, it becomes MRT, because represents the real mean residence time in the body • MRT, excludes the molecules present at the absorption site • MRT = 1/2 where is the elimination rate constant Otherwise V V Thus strongly rely on the availability of good estimate of kand ka! Vss from MRT concept What about after an oral administration? • It can be demonstrated that V.CE- MRT This relationships makes the estimation Vss model independent • MRT after an oral administration will be the sum of the mean residence time in the body and the mean residence time at the absorption site (MAT) MRT MAT + MRT • Then MAT can be estimated by simple difference, if MRT is known from a previous bolus administration MAT = MRT - MRT • MAT is a robust and easy to estimate parameter • MAT Is a measure of absorption rate: 1/MAT • MAT can be used to compare absorption rate across several formulations 12 13
Mean Dissolution Time (MDT) Disadvantage • The mean dissolution time (MDT) is the time required for a drug molecule administered as a solid to dissolve at the absorption site • MAT can be partitioned into MOT and the mean time for absorption of dissolved drug (dd) (MAT MAT = MOT + MAT • Since an orally administered aqueous solution of drug does not require in vivo dissolution, it follows that the MAT resulting from such a solution equals MDL Then MOT - MATMAT • This is one of the simplest methods to estimate in vivo dissolution • AUMC estimation may not be accurate • Why? low concentration dat when the perimentare by targetime values so they have a big pictorial UMC • This amplifies the experimental error in the computation of AUMC Example Drug Xised to ne samo su ndio si BBC Summary MRT • MRT can be applied to a variety of problems in PK/PO... MRT at the effectie • MRT above the MC Their implementation it straightforward • MRT require cely the calculation of AC and ALMC • Numerical fitting is not required • Any tyre of concentration time profile can be analved with this method • The results are robust and reproducible 20 1ST w Estimate RT for each annan 2. Catinale for new MOT 15
Estimate MRT for each administration Estimate MDT MRT 997 43 233 Dissolution of the tablet MD.-MRT MRT. MRT 45 981 5082 MRZ = 6.0 MDT 60-45-15 848 Estimate MAT for the oral solution and the oral tablet Example 2 MAT - MRT MRT The MOT is estimated for three different oral formulations of drug X a, b, and the • MOT 0.53, MOT = 171, MOT, = 2.03 • Which has the longer in Wivo Giolition time? MAT =4.5-4.3 0.2
The Main Non-compartmental Parameters 22 Vz 11/22 CL = F.Dose F.Dose AUMC VSS = AUC2 AUC AUMC MRT = AUC Vss = CL. MRT MRT) = 1/k MAT = 1/kg Conclusions • NCA is a method to obtain basic PK parameters using a simpler mathematical approach compared to the compartmental models Rate Tmak, K, MAT Absorption Distribution Elimination first order) Extent 5. AUC Cmax V Vss, V2 FxDose 18