REVIEW

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 THE PHARMACOKINETICS PARAMETERS

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 THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION

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 THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION

❑ The application of time course of drug concentration:

❑ The velocity of absorption depend on route of administration
❑ Rapid absorption → Shorter Tmax → Higher Cmax → earlier Cp fall
❑ AUC: determine the bioavailability F of drug

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION – SINGLE DOSE

❑ Therapeutic window: concentration range that provide efficacy without

toxicity.
❑ The intensity drug effect related to Cp: MEC ≤ Cp ≤ MIC or MEC (adverse)
❑ Duration of drug effect: length of time the drug level above MEC
❑ Single dose: Lag period → Onset → peak → decline → the drug effect
disappear.
❑ This time course reflect the changes in drug’s concentration ad determined
by the absorption, distribution and elimination.

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

❑ MULTIPLE DOSING: in long-term therapy should determine the amount and frequency of drug administration to
achieve optimal therapeutic effects.
❑ MEC ≤ Cp ≤ MIC or MEC (adverse)
❑ In general:
➢ C low = concentration produces about half the greatest possible therapeutic effects
➢ C high = concentration with no more than 5-10% patients experience toxic effect
➢ Some drugs C high ≤ 2 C low: patients may benefit from exceed concentrations and some may suffer significant toxicity
at lower values (Digoxin)

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

❑ The rise and fall of Cp will be determined by : T1/2 and dose interval
❑ The shorter dose interval related to T1/2 → drug accumulation
❑ Drug intake occurs before the preceding dose id eliminated
completely → Next dose will add to residual amount remain in the
body.
❑ At given dose frequency → drug dose not accumulate and a steady
state Concentration (Css) is reach.

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

The steady state level can be achieved by:

➢ Intravenous infusion : the Css level is determined by infusion rate
➢ Oral administration: divide total dose into several individual doses
→ Css average show little fluctuation

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

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THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION –MULTIPLE DOSING

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 THE THERAPEUTIC GOAL

❑ The efficacy and toxicity depend on:

➢ Drug concentration Cp
➢ Drug dosage
➢ Frequency of administration
❑ For drugs have small differences between MEC and MTC (Digoxin, Theophylline, Lidocaine, Aminoglycosides,
Cysclosporin, Tacrolimus, Warfarin…) → Cp associated with effective therapy has been defined.
❑ The steady – state concentration of drug in plasma must be chosen. (Css target)
❑ The dosage is computed that is expected to achieve Css target
❑ Drug concentration are subsequently measured and dosage is adjusted if necessary

THE THERAPEUTIC GOAL: MAINTAIN STEADY-STATE DRUG LEVELS WITHIN THE THERAPEUTIC WINDOW

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 THE TIME COURS: THE CHANGES IN DRUG’S CONCENTRATION

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DESIGN AND OPTIMIZE DOSAGE REGIMENS

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 DESIGN AND OPTIMIZE DOAGE REGIMEN

REQUIREMENTS
- Drug decision
- Pharmacokinetics parameters: F, t1/2, VD, CL
- Therapeutic range/ therapeutic window/ therapeutic index : MEC – MTC
- Pathology and physiology conditions

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 DESIGN AND OPTIMIZE DOAGE REGIMEN

1. Determine Dosage (Dose)

2. Determine Dosage Frequency (T)

3. Rout of administration

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 1. DETERMINE DOSAGE

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 1. DETERMINE DOSAGE

𝐹. 𝐷𝑜𝑠𝑒 𝐹. 𝐷𝑜𝑠𝑒 1.44. 𝑇 1ൗ2 . 𝐹. 𝐷𝑜𝑠𝑒

𝐶𝑠𝑠 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 = = =
𝐶𝐿. 𝑇 𝑘. 𝑉𝑑. 𝑇 𝑉𝑑. 𝑇

𝐶𝑠𝑠 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 . 𝑉𝐷. 𝑇

𝐷𝑜𝑠𝑒 =
1.44𝑥 𝑇 1ൗ2 𝑥 𝐹

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 1. DETERMINE DOSAGE

𝐶𝑚𝑖𝑛 ≤ 𝐶𝑠𝑠 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 ≤ 𝐶𝑚𝑎𝑥

𝐹.𝐷𝑜𝑠𝑒 1 𝐹.𝐷𝑜𝑠𝑒 𝑒 −𝑘𝑇

𝐶𝑚𝑎𝑥 = × 𝐶𝑚𝑖𝑛 = ×
𝑉𝑑 (1−𝑒 −𝑘𝑇 ) 𝑉𝑑 (1−𝑒 −𝑘𝑇 )

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 1. DETERMINE DOSAGE

DOSE (D)
DOSE FREQUENCY (T)

CSS AVERAGE

INCREASE: DECREASE:
DOSE: INCREASE DOSE: DECREASE
T: DECREASE T: INCREASE
𝐷1 𝐷2
NO CHANGE: =
𝑇1 𝑇2
 1. DETERMINE DOSAGE

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 1. DETERMINE DOSAGE

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 2. DETERMINE T

Cmax = MTC ; Cmin = MEC DOSE FREQUENCY (T)

DOSE FREQUENCY (T) DOSE (D)

1 𝐶𝑚𝑎𝑥
𝑇 = 1.44 𝑥 𝑇 ൗ2 𝑥 𝐿𝑛 𝐷𝑜𝑠𝑒 = 𝐶𝑚𝑎𝑥 𝑥 𝑉𝐷 𝑥 (1 − 𝑒 −𝑘𝑇 )
𝐶𝑚𝑖𝑛

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 3. DETERMINE ROUT OF ADMINISTRATION

Parenteral Extravascular
❑ Forms: tablet, liquid, solution, cream, aerosol…
Intravascular: Enteral
➢ Intravascular injection (IVB bolus) ➢ Buccal ❑ Target: local or system
➢ Intravascular infusion (IVF) ➢ Sublingual
❑ Speed: slow – fast
Intramuscular (IM) ➢ Oral PO
Subcutaneous injection (SC) ➢ Rectal ❑ Rout administration: right and safe
Inhalation
Transdermal

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 DESIGN AND OPTIMIZE DOAGE REGIMEN

F VD CL T1/2

𝐹𝑥 𝐷𝑜𝑠𝑖𝑛𝑔 𝑅𝑎𝑡𝑒
𝐶𝐿 =
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑐𝑖𝑟𝑐𝑢𝑙𝑎𝑡𝑖𝑜𝑛 𝐷𝑜𝑠𝑒 𝐶𝑠𝑠
𝐹= 𝑉𝑑 = 𝑇1/2 = 0.693/𝑘
𝐷𝑜𝑠𝑒 𝐶𝑝 𝐹𝑥 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑒
𝐶𝐿 =
𝐶𝑠𝑠

𝐴𝑈𝐶 𝑃𝑂 𝐶𝐿 𝑥 𝑇1/2 0.693 𝑉𝑑 0.693 𝑉𝑑

𝐹= 𝑉𝑑 = 𝐶𝐿 = 𝑇1/2 =
𝐴𝑈𝐶 𝐼𝑉 0.693 𝑇1/2 𝐶𝐿

𝐴𝑈𝐶 𝑡𝑒𝑠𝑡 𝐶𝐿
𝐹= 𝑉𝑑 = 𝐶𝐿 = 𝑘 𝑥 𝑉𝑑
𝐴𝑈𝐶 𝑠𝑎𝑚𝑝𝑙𝑒 𝑘
 DESIGN AND OPTIMIZE DOAGE REGIMEN

Css average 𝐹. 𝐷𝑜𝑠𝑒 𝐹. 𝐷𝑜𝑠𝑒 1.44. 𝑇 1ൗ2 . 𝐹. 𝐷𝑜𝑠𝑒

𝐶𝑠𝑠 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 = = =
𝐶𝐿. 𝑇 𝑘. 𝑉𝑑. 𝑇 𝑉𝑑. 𝑇

𝐶𝑠𝑠 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 . 𝑉𝐷. 𝑇 𝐷1 𝐷2

Dose 𝐷𝑜𝑠𝑒 = =
1.44𝑥 𝑇 1ൗ2 𝑥 𝐹 𝑇1 𝑇2

𝐶𝑚𝑎𝑥
T 𝑇 = 1.44 𝑥 𝑇 1ൗ2 𝑥 𝐿𝑛 𝐷𝑜𝑠𝑒 = 𝐶𝑚𝑎𝑥 𝑥 𝑉𝑑 𝑥 (1 − 𝑒 −𝑘𝑇 )
𝐶𝑚𝑖𝑛

𝐹.𝐷𝑜𝑠𝑒 𝑒 −𝑘𝑇
Css min 𝐶𝑚𝑖𝑛 = x
𝑉𝑑 (1−𝑒 −𝑘𝑇 )

𝐹.𝐷𝑜𝑠𝑒 1
Css max 𝐶𝑚𝑎𝑥 = 𝑉𝑑
× (1−𝑒 −𝑘𝑇 )

Tss 𝑇𝑠𝑠 = 4 𝑥 𝑇1/2

Bài tập 1:
Liều duy trì DM cùa Digoxin cho bệnh nhân 60kg chức năng thận bình thường là 0.5mg/ngày. Digoxin có thời gian bán
thải là 0.95 ngày; VD = 306L. Sinh khả dụng Digoxin là 0.56
a/ Tính nồng độ thuốc khi ổn định?
b/ Nếu nồng độ hiệu quả là 1-2 ng/mL thì liều như vậy đã đủ chưa?
c/ Tính nồng độ khi ổn định nếu Digoxin bệnh nhân dùng thuốc dạng siro (F=100%)

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Bài tập 2:
Một kháng sinh có thời gian bán thải là 2 giờ; VD= 200mL/kg; MEC =2ug/mL; MTC =16ug/mL. Một bác sĩ chỉ định
dung thuốc này với liều 250mg tiêm tĩnh mạch mỗi 8 giờ.
a/ Liều này có phù hợp cho bệnh nhân 23 tuổi, nặng 80kg và có CL creatinine = 122mL/phút?
b/ Anh chị có kiến nghị gì về chế độ dung thuốc cho bệnh nhân này? Vì sao?

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Bài tập 3:
Tính chế độ liều dùng để uống một thuốc trợ tim trên bệnh nhân 63 tuổi, nặng 68kg. Thuốc có thời gian bán thải
là 30 giờ; VD=4L/kg; F=0.8. Cho biết liều điều trị trong khoảng 0.001 -0.002ug/mL.
a/ Trên thị trường thuốc này ở dạng viên nén loại 0.075; 0.15 và 0.3mg/ viên. Bệnh nhân này dùng 1 liều mấy
viên?
b/ Lợi hay bất lợi nếu bệnh nhân này dùng liều nhỏ hơn và khoảng cách liều dùng ngắn hơn?
c/ Có nên dùng liều tấn công không? Tại sao? Nếu dung thì dùng liều bao nhiêu?

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 HOMEWORK

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 HOMEWORK

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 HOMEWORK

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