6- Extravascular notes PDF

Preview

Summary

Extravascular administration (for one compartment model)Leonid Kagan, Ph.Department of Pharmaceutics Ernest Mario School of Pharmacy, [email protected]:721:430 | Extravascular | 2020 Leonid Kagan PhD | Rutgers University | 1Objectives for This Lecture Define absorption rate constant, a...

Description

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Extravascular administration (for one compartment model) Leonid Kagan, Ph.D. Department of Pharmaceutics Ernest Mario School of Pharmacy, Rutgers

[email protected] 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

1

Objectives for This Lecture • Define absorption rate constant, absorption and elimination phases, bioavailability and extent of absorption, flip-flop, lag time, Cmax, Tmax • Absorption-rate limited kinetics vs. elimination-rate limited kinetics • Estimate PK parameters using plasma data • Calculate plasma concentration at different times following extravascular dosing • Understand the basic principles for oral absorption 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

2

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Extravascular Administration • • • • • • • • •

Oral (PO) Subcutaneous (SC/SQ) Intramuscular (IM) Inhalation Intranasal Sublingual Buccal Transdermal Rectal

Extravascular dose

Rowland & Tozer, 2011 Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

3

Oral Dosing • Variety of formulations (dosage forms): tablet, capsule, oral solution, suspension, syrup, emulsion… • Controlled-release (modified-, sustained-) • Self-administered • Convenience • Patient compliance

• Often incomplete bioavailability

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

4

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

PK profile after extravascular dose Rate of absorption

!" = %& ' () − % ' " !#

=

Cmax

Rate of elimination

Absorption Phase Rate of absorption > Rate of elimination

Post-absorption phase Rate of absorption < Rate of elimination

Elimination phase Rate of absorption < Rate of elimination

Tmax

Later rate of absorption = 0 Shargel & Yu. Applied Biopharmaceutics & Pharmacokinetics, 7e; 2016 Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

5

One compartment distribution model with absorption Absorption site (GI)

Absorption rate constant

ka V

*=

'( ) + ) ,-./ 01)2 / − / 013 )2 '( − '

4=

'( ) + ) ,-./ 01)2 / − / 013 )2 5 ) '( − '

CL or k

!"# !$

= −'( ) "#

!* = '( ) "# − ' ) * !$

30:721:430 | Extravascular | 2020

ln 4 = ln

'( ) + ) ,-./ + ln / 01)2 − / 013 )2 5 ) '( − '

Leonid Kagan PhD | Rutgers University |

6

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Determination of Absorption Rate Constant • The method of residuals (also known as feathering, peeling, or curve stripping) is a commonly employed technique for resolving a curve into various exponential terms – Back-extrapolate the terminal phase for the early time points – Calculate residual between the extrapolated line and actual concentration – Determine the slope of the secondary line

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

7

Terminal slope and Intercept ln # = ln

%& ' ( ' )*+, + ln , 01'2 − , 013 '2 - ' %& − %

If ka>>k, when time is large

Slope = k

, 13 '2 → 0

ln # = ln

%& ' ( ' )*+, + ln , 01'2 - ' %& − %

ln # = ln

%& ' ( ' )*+, −%'6 - ' %& − %

Intercept =

Rowland & Tozer, 2011 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

8

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Method of Residuals

#$ % & % '()* -.%/ * − * -.0 %/ + % #$ − #

!1 =

#$ % & % '()* -.%/ * + % #$ − #

k

Rowland & Tozer, 2011 Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

9

Method of Residuals Backextrap & residual meet later than 0 hrs—! Dellay form when u swallpw tablet & when it gets absorbed! ! Concentration s can be calculated but using T-T0 ! T0 = time after lag

! ! !

!=

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

ka

k

This k slope ! is = the terminal slope in eliminated- rate !1 = limited kinetics

a minimum of three points should be used to define the straight line 30:721:430 | Extravascular | 2020

#$ % & % '()* -.%/ * − * -.0 %/ + % #$ − # #$ % & % '()* -.%/ * + % #$ − #

!1 − ! =

#$ % & % '()* -. %/ * 0 + % #$ − #

Leonid Kagan PhD | Rutgers University |

10

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Rate-Limiting Step Elimination-rate limited

Absorption-rate limited (flip-flop)

Your terminal slope is dictated by Ka and the ka > k secondary line is actually k Ka Rate of absorption faster- MOST COMMON (opposite from what was seen above)

k

ka < k

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

12

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Events at the peak (Tmax and Cmax) !" %& ' ( ' )*+, −% ' , /0'1 + %& ' , /03 '1 = - ' %& − % !#

At Tmax rate of input is equal to rate of output

No rate of change

% ' , /0'5637 = %& ' , /03 '5637

89&:

% ln & % = %& − %

!" = 0, therefore !#

Tmax, Cmax same= bioequiv

Tmax is dose independent

%& ↑− −89&: ↓ If the rate of absorption is faster, you will reach tmax in less time

"9&: =

( ' )*+, /0'5637 , -

89&: ↓− −"9&: ↑ Less time, then C max is higher

30:721:430 | Extravascular | 2020

Tmax

Leonid Kagan PhD | Rutgers University |

13

Effect of k and ka on Cmax and Tmax

Initial value

If k remains the same but ka is increased, then you will see point B instead of A so Tmax becomes shorter, and Cmax becomes higher!

Point C— shorter tmax, but lower Cmax bc increased K (refer to equation for Cmax) 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

14

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

What if absorption is constant, but disposition changes? If F, ka, and Vd are constant, but CL is reduced • • • • •

AUC increases Cmax increases Tmax increases T1/2 increases kel decreases

If F, ka, and CL are constant, but Vd is increased • • •

AUC is the same Cmax decreases Tmax increases

15

30:721:430 | Extravascular | 2020

AUC after extravascular dosing '

!"# = % # ( )* # = &

=

+, ( - ( ./01 ' 45(6 − 1 457 (6 )* = % 1 2 ( +, − + &

+, ( - ( ./01 1 1 - ( ./01 - ( ./01 − = = #9 2 ( +, − + + +, 2(+

!"# =

- ( ./01 #9

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

16

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Absorption delay – Lag Time (t0) •

The time delay prior to commencement of first-order absorption is known as lag time

the drug

Lag time— no absorption! Takes time to get to small intestine if thats where the drug is absorbed (enteric)

•

The lag time can be determined graphically if the two residual lines obtained by feathering the plasma concentration–time curve intersect at a point where t > 0

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

17

Multiple extravascular dose

!=

* -.%/ * -.2 %/ #$ % & % '()* − + % #$ − # 1 − * -.%1 1 − * -.2 %1

ln 34$5 =

#$ % 1 − * -.%1 # % 1 − * -.2 %1 #$ − #

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

18

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Assessment of PK parameters from extravascular data • Extravascular data only allow for determination of a few PK parameters: AUCev, terminal slope, Cmax, Tmax • Determination of CL and VD requires F – For oral dosing CL/F (oral CL) and Vd/F (oral V) are sometimes reported

• To distinguish between k and ka prior knowledge of the true elimination rate is required (absorption- or elimination-rate limited)

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

19

Causes of loss in oral bioavailability F = FF ∙ FG ∙ FH F – total bioavailability FF – the fraction entering the intestinal wall tissue Into enterocytes FG – the fraction that survives degradation in the intestinal wall FH – the fraction that survives degradation (excretion) in the liver Example: If 50% of the drug is lost at each step The bioavailability is F = 0.5 ∙ 0.5 ∙ 0.5 = 0.125 (or 12.5%) 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

20

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Bioavailability • After extravascular administration, the dose that gains access to the systemic circulation might be less than 100%

AUCev Bioavailability = F =

AUCIV

Doseev DoseIV

Major assumption is that clearance is constant and independent on the mode of administration

Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

21

Linear PK • AUC and Cmax (or C0) are dose-proportional Double dose, double AUC, etc • CL and Vd are independent of dose level • For extravascular dose, Tmax is independent of dose level • t1/2 is constant

Rowland & Tozer, 2011 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

22

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

AUC at Steady State When F and Vd are unknown, it is still possible to design a dosage regimen

F ⋅ Dose = CL ⋅ AUC

For single dose:

During steady state: τ

AUCss ( 0 → τ ) = ∫ C ⋅ dt = 0

=

F ⋅ Dose = CL ⋅ Cav,ss τ

Cav,ss =

AUC ( single dose) τ

% e−k⋅τ 1 ( DM − *= ' V ⋅ (1− e−k⋅τ ) & −k −k )

DM DM = AUC ( single dose, 0 → ∞) = V ⋅ k CL

Rowland & Tozer, 2011 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

23

What governs oral absorption • Anatomy and physiology of the gastrointestinal tract • Physicochemical properties of the drug • Design of the dosage form

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

24

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Region differences in the GI tract l l l l l

Transporters Enzymes Area Permeability Amount of fluid

Absorption capacity and characteristics

Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

25

Stomach • There is little absorption in the stomach • Environment: – The human stomach secretes 1-1.5L of gastric juice per day – highly acidic and reach in enzymes. – The pH ranges from ~ 1.5-2 (fasting) to 3-6 (fed). – This environment affects solubility, ionization and stability of drugs

• Motility: – Gastric emptying time is highly variable (transit time 0-2h) – Presence of food, size of the meal, as well as food or formulation components will greatly affect gastric emptying time, and therefore the rate of absorption of drugs 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

26

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Small intestine The major region for drug absorption Large area and highly perfused

Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

27

Colon • There is a pH drop from the terminal ileum to the ascending colon • Colonic bacteria • Relatively low amount of fluids • Low absorption area – No villi – Microvilli are present

• Long residence time – important for controlled release dosage forms Clarke et al. Pharmacol Rev 71:198–224 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

28

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Gastric emptying time and GI motility

Large particles, including tablets and capsules, are delayed from emptying for 3–6 hours by the presence of food in the stomach.

The rate and extent of oral absorption, and the resulting PK profile can be very different between fasted and fed state When you dont have anything in your stomach, it goes through motility cycles! No motility (for 60min), then small contractions ever 10/20 minutes! When you take a liquid dosage form it will eliminate almost immediately, 1st order (going through the pyloric phinc)! Leonid Kagan PhD | Rutgers University | 29 30:721:430 | Extravascular | 2020 If you swallow a tablet that wont disintegrate it will stay in the stomach a long time it will take a while before reaching phase 4 or 5 motility cycle (gastric emptying happening)! If you eat something there is constant motility against the pyloris may empty right away or take several hours (if you had a large meal)

Main absorption mechanism • Transport across cell membranes by passive diffusion Transcellular absorption

Rate of diffusion

!" % & ' & () = +,- − +/ !# ℎ

!" = 0 & +,!#

D – diffusion coefficient A – surface area of membrane Kp – lipid-water partition coefficient of drug in the biological membrane that controls drug permeation h – membrane thickness CGI-Cp – concentration gradient

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

30

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

pH in human gut

Stomach

30:721:430 | Extravascular | 2020

* RTC – radiotelemetry capsule

Leonid Kagan PhD | Rutgers University |

31

pH in human gut • Drug molecules are predominantly weak acids or weak bases • However, drugs penetrates the lipophilic membrane in their unionized (non-polar) state • Therefore, pH in the lumen is very important for absorption • Henderson and Hasselbalch equation

30:721:430 | Extravascular | 2020

!" = !$% + log

*+ "*

Leonid Kagan PhD | Rutgers University |

32

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

pH in human gut •

Based on pH-partition hypothesis, an acidic drug would penetrate the membrane better from acidic environment (stomach), but solubility would be higher in basic environment (small intestine)

•

Based on pH-partition hypothesis, a basic drug would penetrate the membrane better from more basic environment (small intestine), but solubility would be higher in acidic environment (stomach)

•

In fact, the absorption of almost all drugs would be faster from small intestine than from stomach (even for weak acids) Bc of surface area and perfusion

– Other important factors: • Total absorption area • Perfusion

•

Therefore, we use pH-partition hypothesis for guideline only rather than trying to predict accurately the drug absorption

•

Permeability/solubility interplay is a very important concept in biopharmaceutics Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

33

Drug transporters in the gut Limit bioavil- Pglyco PRot, BCrP, Mrp2! Help bioavail- PEPT1

Using ATP, some using Conc gradient etc!

Val- Acyclovir— pro drug, going through PEPT1

Shargel & Yu. Applied Biopharmaceutics & Pharmacokinetics, 7e; 2016. MacDougall et al., J Antimicrob Chemother (2004) 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

34

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Examples of transporters facilitating drug absorption

Shargel & Yu. Applied Biopharmaceutics & Pharmacokinetics, 7e; 2016

30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

35

Relative expression of transporters in human intestine

Certain regions have more some have less! ! PEPT1 has more in ileum, nothing in colon so if you give a dosage form that is released in colon, it wont be absorbed, no transporter

Englund et al., Eur J Pharm Sci 26: p.269-277, 2006. 30:721:430 | Extravascular | 2020

Leonid Kagan PhD | Rutgers University |

36

“Absorption Windows” Small intestine transit Colon

Stomach

Kt1

Kt2

S

Kt3

USI

Kt4

LSI

LI

? parts of intestine! Diff Absorption from diff Central compartment K21 regions is di ff, this may P Central Distribution have diff pk behavior— ! K12 Elimination K10 ! Peripheral compartment ! Immediate release— Intestinal transit of Phenol red release fast and higher conc. But if you give it as 100 Stomach Upper Colon 350 a conventional controlled small intestine IR 80 release dosage form & is Lower 300 Conventional not CRabsorbed in colon, small intestine Eventually after 6 hrs most250 60 your bioavail drops! of drug is transferred from 200 ! stomach to colon Gastro-retentive CR 40 150 ! But if you modify using 100 20 gastrorentitive CR, you will 50 have increased bioavail/ 0 0 1 2 3 4 5 6 0 absorption because this is 0 120 240 360 480 600 720 840 960 1080 1200 1320 1440 Time (h) Time (min) designed to have increased residence in Sawamoto et al. J Pharm Pharmacol 1997; Kagan et al. Eur J Pharm Biopharm 2008 upper regions Absorption

Ka3

Ka4

Percent of dose

AT plasma concentration (ng/mL)

Ka2

Leonid Kagan PhD | Rutgers University |

30:721:430 | Extravascular | 2020

37

Drug absorption m...