PHA 337 - Multiple Dosing and Drug Accumulation L9

What is multiple dosing?

Administration of several doses of a drug over time

What is drug accumulation?

The buildup of drug in the body from previous doses

Why do most continuously administered drugs accumulate?

Because some drug remains in the body when the next dose is given

What types of drugs may only need single doses?

Hypnotics, antiemetics, and pre-op sedatives

What determines accumulation to steady state?

Half-life and dosing interval

What does τ represent?

Dosing interval

What does t represent in multiple dosing equations?

Time elapsed since the last dose

What does n represent in multiple dosing equations?

Number of doses

What happens when the dosing interval is long compared with half-life?

Little accumulation occurs

What happens when the dosing interval is equal to the half-life?

The drug accumulates more

What happens when the dosing interval is shorter than the half-life?

The drug accumulates even further

Does increasing the dose change half-life?

No

What controls the time to steady state?

Half-life

How long does it generally take to reach steady state with multiple dosing?

About 5.5 half-lives

For gentamicin with a half-life of 2 hours given every 8 hours, when is steady state reached?

After about 10-12 hours, or by the second dose

Why does gentamicin given every 8 hours with a 2-hour half-life accumulate very little?

The dosing interval is much longer than the half-life

If a drug is dosed every half-life, what happens to Amax at steady state?

It becomes about double the first-dose Amax

If first-dose Amax is 100 mg and the drug is dosed every half-life, what is steady-state Amax?

About 200 mg

What is Css max?

Maximum steady-state concentration after a dose

What is Css min?

Minimum steady-state concentration before the next dose

When does Css max occur after intermittent IV bolus dosing?

Immediately after the dose

When does Css min occur after intermittent IV bolus dosing?

Just before the next dose

At Css max for IV bolus dosing, what is t?

t = 0

At Css min for IV bolus dosing, what is t?

t = τ

At t = 0, what does e⁻ᴷᵗ equal?

1

At steady state, what happens to e⁻ⁿᴷτ as n approaches infinity?

It approaches zero

What does the multiple-dose IV bolus equation calculate?

The concentration after n doses at any time after the last dose

What equation gives concentration after n intermittent IV bolus doses?

Cn = (D/V)[(1 - e⁻ⁿᴷτ)/(1 - e⁻ᴷτ)]e⁻ᴷᵗ

What equation gives steady-state concentration at any time after an IV bolus dose?

Css = (D/V)[1/(1 - e⁻ᴷτ)]e⁻ᴷᵗ

What equation gives Css max for intermittent IV bolus dosing?

Css max = (D/V)[1/(1 - e⁻ᴷτ)]

What equation gives Css min for intermittent IV bolus dosing?

Css min = (D/V)[1/(1 - e⁻ᴷτ)]e⁻ᴷτ

What is the difference between Css max and Css min?

Css max is right after the dose; Css min is right before the next dose

What is the key idea of intermittent IV bolus accumulation?

Each new dose is added to drug remaining from previous doses

What happens to peak and trough as repeated doses continue?

They rise until steady state is reached

At steady state, what happens to peak and trough values?

They repeat the same pattern each dosing interval

What is intermittent IV infusion?

Repeated IV infusions given over a set infusion time

What does t′ represent in intermittent IV infusion equations?

Duration of infusion

What does T represent in intermittent IV infusion equations?

Time after the infusion is stopped

What is R₀ for intermittent IV infusion?

Dose divided by infusion time

What is the equation for R₀?

R₀ = D/t′

For intermittent IV infusion, when does Css max occur?

At the end of the infusion

For intermittent IV infusion, when does Css min occur?

Just before the next dose

For intermittent IV infusion, what is T at Css max?

T = 0

At Css max for intermittent IV infusion, what does e⁻ᴷᵀ equal?

1

For intermittent IV infusion, what does Css min include?

Decline after the infusion ends until the next dose

For intermittent IV infusion, what equation gives Css max?

Css max = [S(D/t′)/(KV)][(1 - e⁻ᴷᵗ′)/(1 - e⁻ᴷτ)]

For intermittent IV infusion, what equation gives Css min?

Css min = [S(D/t′)/(KV)][(1 - e⁻ᴷᵗ′)/(1 - e⁻ᴷτ)]e⁻ᴷ(τ-t′)

What is the main difference between IV bolus and intermittent IV infusion equations?

Intermittent infusion accounts for infusion time

Why must infusion time be accounted for in peak/trough problems?

Because peak and trough are drawn relative to the end of infusion and next dose

In aminoglycoside monitoring, when is the peak often drawn?

About 30 minutes after the end of infusion

In aminoglycoside monitoring, when is the trough often drawn?

About 30 minutes before the next dose

Why is the time between peak and trough important?

It is used to calculate K and half-life

What equation is used to calculate K from peak and trough levels?

K = ln(Cpeak/Ctrough)/Δt

What equation is used to calculate half-life from K?

t½ = 0.693/K

In the amikacin example, what dose was given?

300 mg

In the amikacin example, what dosing interval was used?

q8h

In the amikacin example, what was the infusion time?

1 hour

In the amikacin example, when was the peak drawn?

30 minutes after the end of infusion

In the amikacin example, when was the trough drawn?

30 minutes before the next dose

In the amikacin example, what was the reported peak?

28 mg/L

In the amikacin example, what was the reported trough?

15 mg/L

In the amikacin example, what was the calculated K?

0.104 hr⁻¹

In the amikacin example, what was the calculated half-life?

6.66 hours

In the amikacin example, what was the calculated V?

17.102 L

In the amikacin example, what was the calculated weighted Vd?

0.244 L/kg

What is weighted volume of distribution?

Volume of distribution divided by body weight

What are the units of weighted volume of distribution?

L/kg

What happens if dosing interval is increased?

Accumulation decreases and trough decreases

What happens if dosing interval is decreased?

Accumulation increases and trough increases

What happens if dose is increased?

Peak and trough increase

What happens if dose is decreased?

Peak and trough decrease

Does changing the dose change the dosing interval?

No

Does changing the dose change K?

No

Does changing the dose change half-life?

No

Does changing the dose change Vd?

No

What is the purpose of changing the dosing interval?

To adjust accumulation and trough concentration

What is the purpose of changing the dose?

To adjust peak concentration

Which is more affected by changing interval: peak or trough?

Trough

Which is more affected by changing dose: peak or trough?

Both increase or decrease proportionally

What is the safest way to reduce a high trough?

Increase the dosing interval

What is the safest way to raise a low peak?

Increase the dose

What does q8h mean?

Every 8 hours

What does q12h mean?

Every 12 hours

What does q24h mean?

Every 24 hours

What does steady state mean in multiple dosing?

The amount of drug given equals the amount eliminated over each dosing interval

At steady state, do concentrations remain completely flat with intermittent dosing?

No, they fluctuate between peak and trough

What is the difference between steady state and constant concentration?

Steady state means repeated peak/trough pattern, not necessarily a flat line

What is the main factor causing accumulation?

Drug remaining from previous doses

If no drug remains before the next dose, will accumulation occur?

No

If a lot of drug remains before the next dose, will accumulation occur?

Yes

What is the main concept behind Css max and Css min?

They define the steady-state peak and trough range

What does a high trough suggest?

Excessive accumulation

What does a low trough suggest?

Less accumulation

For intermittent dosing, what happens after each dose?

Concentration rises then falls

For intermittent dosing, what happens just before the next dose?

Concentration reaches its minimum

For intermittent IV infusion, when does concentration rise?

During the infusion

For intermittent IV infusion, when does concentration fall?

After the infusion stops