Multiple dosage regimens, Bio availability and Bioequivalence

1. Biopharmaceutics II:
Multiple dosage regimens
Sonia Barua, PhD
Assistant professor,
Department of Pharmacy,
USTC, Chittagong

2. • What is Biopharmaceutics
 The physical and chemical properties of drugs and drug products and their pharmacokinetic properties
and the fate of drugs after the systemic circulation.
• What is Multiple dosage regimens
To maintain prolonged therapeutic activity, many drugs are given in a multiple-dosage regimen.
Figure 1

3. Properties of MDR:
By far though, most drugs are given in several doses, for example, multiple doses to treat
chronic disease such as arthritis, hypertension, etc. After single-dose drug administration,
the plasma drug level rises above and then falls below the minimum effective
concentration (MEC), resulting in a decline in therapeutic effect.
 To treat chronic disease, multiple-dosage or IV infusion regimens are used to maintain
the plasma drug levels within the narrow limits of the therapeutic window (eg,
plasma drug concentrations above the MEC but below the minimum toxic concentration
or MTC) to achieve optimal clinical effectiveness. These drugs may include
antibacterials, cardiotonics, anticonvulsants, hypoglycemics, antihypertensives,
hormones, and others.
 Ideally, a dosage regimen is established for each drug to provide the correct plasma level
without excessive fluctuation and drug accumulation outside the therapeutic
window.

4. Toxicity
Plasmadrugconcentration
MTC
MEC
Therapeutic window
Time (h)
Figure 2

5. Criteria for optimum dosage regimen:
 The plasma levels of drug given must be maintained within the
therapeutic window.
 ■ Ex. The therapeutic range of theophylline is 10-20gg/L. So, the best is to
maintain the CP around 15gg/L.
Should be convenient to the patient
 ■ It is difficult to take I.V. injection every hour or one tablet every 2 hour, this
lead to poor compliance.
Multiple dosage regimens

6. • In calculating a multiple-dose regimen, the desired or target plasma drug concentration must be related to a
therapeutic response, and the multiple-dose regimen must be designed to produce plasma concentrations
within the therapeutic window.
• There are two main parameters that can be adjusted in developing a dosage regimen: (1) the size of the drug
dose and (2) τ, the frequency of drug administration (ie, the time interval between doses).

7. • To calculate a multiple-dose regimen for a patient or patients, pharmacokinetic parameters are first
obtained from the plasma level–time curve generated by single-dose drug studies. With these
pharmacokinetic parameters and knowledge of the size of the dose and dosage interval (τ), the
complete plasma level–time curve or the plasma level may be predicted at any time after the beginning
of the dosage regimen.
• For calculation of multiple-dose regimens, it is necessary to decide whether successive doses of drug
will have any effect on the previous dose. The principle of superposition assumes that early doses of
drug do not affect the pharmacokinetics of subsequent doses. Therefore, the blood levels after the
second, third, or nth dose will overlay or superimpose the blood level attained after the (n – 1)th dose. In
addition, the AUC = for the first dose is equal to the steady-state area between doses, ie, as shown in
Figure. and equation AUC=

9. • The superposition principle can be used when all the PK processes are
linear.
• That is when distribution, metabolism, and excretion (DME) processes are
linear or first order.
• Thus, concentrations after multiple doses can be calculated by adding
together the concentrations from each dose. Also, doubling the dose will
result in the concentrations at each time doubling.
Superposition Principle

10. • Principle of superposition
• The basic assumptions are
(1) that the drug is eliminated by first-order kinetics and
(2) that the pharmacokinetics of the drug after a single dose (first dose) are
not altered after taking multiple doses.

11. • Drug accumulation:
• Drug accumulationis occurred when second dosing interval in case of multipledosage regimen is
beyond the completedrug elimination of the previous dose.
• The shorter the dosing interval relative to the elimination half-life, the larger will be the residual
amount of drug to which the next dose is added and the more extensively will the drug accumulate
in the body.
• The time required to reach steady state accumulation duringmultiple constantdosing dependson
the rate of elimination.
• When elimination is impaired (e.g., in progressive renal insufficiency), the mean plasma level of
renallyeliminated drugs rises and may enter a toxic concentrationrange.

12. • Drug Accumulation Index
• Accumulation is affected by the elimination half-life of the drug and the dosing interval. The index
for measuring drug accumulationR is
Substitutingfor Cmax after the first dose and at steady state yields
1
2

13. Accumulation: Administered drug is not completely
eliminated during interval Steady state: drug intake equals
elimination during dosing interval
Plasma-time Curve profile

14. Irregular drug
uptake
Time course of drug concentrationin bloodduring regularintake

15. Accumulationt1/2 half lives
Drug accumulation is similar in time course to the time course of drug elimination. Essentially all
drug is eliminated after 4 half-lives. The absorption half-life can be used to predict the time
(Tmax) of peak concentration for many drugs
An equation for the estimation of the time to reach one-half of the steady-state plasma levels or
the accumulation half-life has been described by van Rossum and Tomey (1968).
For IV administration,ka is very rapid (approaches ∞); k is very small in comparison to ka
and can be omitted in the denominatorof Equation3. Thus, Equation3 reduces to
3
4

16. Missed dose or dose adjustment
• Missed dose generally implies with missing or omitted of one or many doses at any time.
• General equation of multipledosage-regimen:
• Generally, if the missing dose is recent, it will affect the present drug level more. If the missing
dose is several half-lives later (>5t1/2), the missing dose may be omitted because it will be very
small.
• Concentrationcontributedby the missing dose is
5
6

17. in which tmiss = time elapsed since the scheduled dose was missed.
Subtracting Equation 5 from Equation 4 corrects for the missing dose as shown in
Equation 7
7
If steady state is reached (ie, either n = large or after many doses), the equation simplifies to
Equation 8. Equation 8 is useful when steady state is reached.
8

18. • Early or Late Dose Administration during Multiple Dosing
When one of the drug doses is taken earlier or later than scheduled, the resulting plasma drug concentration can still be
calculated based on the principle of superposition.
Intermittent Intravenouse Infusion
Intermittent IV infusion is a method of successive short
IV drug infusions in which the drug is given i) by IV
infusion for a short period of time followed ii) by a
drug elimination period, then followed iii) by another
short IV infusion (Fig. 9-4). In drug regimens involving
short IV infusion, the drug may not reach steady state.
The rationale for intermittent IV infusion is to prevent
transient high drug concentrations and accompanying
side effects. Many drugs are better tolerated when
infused slowly over time compared to IV bolus dosing
Examples book
9
Plasma drug concentrationafter two doses by IV infusion.

19. Repetitive intravenous injections
• After a single dose administration we assume that there is no drug in the body before the drug is
given and that no more drug is going to be administered. However, in the case of multiple dose
administration we are expected to give second and subsequent doses before the drug is
completelyeliminated.
• Thus ACCUMULATION of the drug should be considered. On repeated drug administration the
plasma concentration will be repeated for each dose interval giving a PLATEAU or STEADY
STATE with the plasma concentration fluctuatingbetween a minimum and maximum value.
Plasma time-curve profile at steady state

20. Multiple oral dose regimens
If the drug is administeredat a fixed dose and a fixed dosage interval, as is the case with many
multiple-doseregimens, the amount of drug in the body will increase and then plateauto a
mean plasma level higher than the peak Cp obtainedfrom the initialdose (Following figures).
10
Amount of drug in the body as a function of time. Equal doses of drug were given
every 6 hours (upper curve) and every 8 hours (lower curve). ka and k remain
constant.

21. The mean plasma level at steady state, Cav , is determined by a
similar method to that employed for repeat IV injections. The
following can be used for finding Cav for any route of
administration
11
VX
12 Simulated plasma drug concentration–time
curves after IV infusion and oral multiple doses
for a drug with an elimination half-life of 4 hours
and apparent VD of 10 L. IV infusion given at a
rate of 25 mg/h, oral multiple doses are 200 mg
every 8 hours, 300 mg every 12 hours, and 600
mg every 24 hours.
Because proper evaluation of F and VD requires IV data, the AUC
of a dosing interval at steady state may be substituted in Equation
11 to obtain

22. The Cav will be predictably higher for drugs distributed in a
small VD (eg, plasma water) or that have long elimination half-
lives than for drugs distributed in a large VD (eg, total body
water) or that have very short elimination half-lives. Because
body clearance (ClT) is equal to kVD, substitution into Equation
11 yields
13
14

23. At steady state, the drug concentration can be determined by letting n equal infinity. Therefore, e-nkt
becomes approximately equal to zero and becomes
The maximum and minimum drug concentrations (Cmax and Cmin ) can be obtained with the
following equations:
15
16

24. • The time at which maximum (peak) plasma concentration (or tmax) occurs following a single oral
dose is
whereas the peak plasma concentration, tp, following multiple doses is given by Equation 9.41.
example
Examples
17
18

25. Loading Dose
With some drugs, especially those with a large volume of distribution, it may be necessary to give a loading dose (a
big dose) initially to get above the minimum effective concentration and get the beneficial effect quickly. In such
situations, a loading dose is used to reach the minimum effective concentration, and then maintenance doses are
given to maintain the minimum effective concentration (bottom, Figure). With a loading dose, the minimum
effective concentration is reached much quicker than using the maintenance dose.
Maintenance doses and loading dose

26. For drugs absorbed rapidly in relation to elimination(k a >> k) and are distributed rapidly, the loading
dose D L can be calculated as follows
For extremely rapid absorption, as when the product of ka is large or in the case of IV infusion, e –ka
becomes approximately zero and 1st equation reduces to :

27. The loadingdose should approximatethe amount of drug containedin the body at steady state. The dose ratio is
equal to the loadingdose divided by the maintenancedose.
As a general rule, the dose ratio should be equal to 2.0 if the selected dosage intervalis equal to the
elimination half-life. shows the plasma level–time curve for dosage regimens with equal maintenancedoses
but different loadingdoses. A rapid approximationof loadingdose, D L, may be estimated from:
Where, C ∞
av is the desired plasma drug concentration, S is the salt form of the drug, and F is the fraction of
drug bioavailability

28. Concentration curves for dosage regimenswith equal maintenance doses (D)
and dosage intervals(τ) and different dose ratios.

29. An example of a drug that is used with a loading dose and maintenance doses is the anti-platelet drug
clopidogrel. Intravenous clopidogrel is given as a loading dose in percutaneous coronary intervention to
prevent clotting straightaway, and this is followed by oral maintenance doses to prevent coagulation, as the
subject recovers from the surgery.
Steady-state concentrations are eventually reached with both maintenance and loading/maintenance dosing
Importance of loading dose
1. To attend quick plasma level.
2. Attain quick action.
3. The main importance of loading dose is average plasma concentration at steady state as quickly as
possible.
4. In some cases loading dose helps to get therapeutic effect quickly

30. Bioavailability & Bioequivalence
• What is Bioavailability?
• The rate and extend to which the active concentration of a drug is available at the
desired site of action (or bloodstream)
• Bioavailability of a drug is largely determined by the properties of the dosage
form, which depend partly on its design and manufacture

31. Types of Bioavailability
Absolute bioavailability (Comparative)
 Bioavailability of drugs after administered
via oral route as compare to IV route
Relative Bioavailability
 Available of drugs administered via oral route and
compare with that of same drug i.e reference
standard or other formulations or routes of the same
drugsFor Single dose

32. where
Fabs is the fraction of the dose absorbed, expressed as a percentage;
AUCpo is the AUC following oral administration;
Div is the dose administered intravenously;
AUCiv is the AUC following intravenous administration; and
Dpo is the dose administered orally
Frel is the relative bioavailability of treatment (formulation) A, expressed as a percentage;
AUCA is the AUC following administration of treatment (formulation) A;
DA is the dose of formulation A;
AUCB is the AUC of formulation B; and
DB is the dose of formulation B.

33. Absolute bioavailability is a ratio of areas under the
curves. IV, intravenous; PO, oral route. C is plasma
concentration (arbitrary units)
A-Oral
B-Rectal
C-Suspension
Plasma-time curve profile of Relative
Bioavailability.

34. The bioavailability of a new investigational drug was studied in 12 volunteers. Each volunteer received
either a single oral tablet containing 200 mg of the drug, 5 mL of a pure aqueous solution containing 200
mg of the drug, or a single IV bolus injection containing 50 mg of the drug. Plasma samples were obtained
periodically up to 48 hours after the dose and assayed for drug concentration. The average AUC values
(0–48 hours) are given in the table below. From these data, calculate (a) the relative bioavailability of the
drug from the tablet compared to the oral solution and (b) the absolute bioavailability of the drug from the
tablet
Problems

35. The relative bioavailability of the drug from the tablet is estimated in the equation below. No adjustment
for the dose is necessary since the nominal doses are the same.
The relative bioavailability of the drug from the tablet is 1.04, or 104%, compared to the solution
The absolute drug bioavailability from the tablet is calculated and adjusted for the dose

36. Because F, the fraction of dose absorbed from the tablet, is less than 1, the drug from the oral
tablet is not completely absorbed systemically, as a result of either poor oral absorption of the
drug itself, formulation effects that reduce oral bioavailability, or metabolism by first-pass effect
(presystemic elimination). The relative bioavailability of the drug from the tablet is
approximately100% when compared to the oral solution.
The comparison between oral solution (little to no formulation effect) and IV administration
gives information on the absorption of the drug

37. Factor influencing Bioavailability:
Pharmaceutical Factors:
I. Drug concentration at site of administration.
II. Surface area of the absorptive site.
III. Drug pKa: Drug solubility: Salts of weakly acidic drugs are highly water soluble, free acidic drugs is
precipitated from these salts is micro crystalline form, which has a faster dissolution rate and
increases bioavailability
IV. Drug molecule size: The rate at which a drug is dissolved can be increased by increasing its surface
area by decreasing its PARTICLE SIZE
V. pH of the surrounding fluid.
VI. The drug formulation (immediate release, excipients used, manufacturing methods, modified release
– delayed release, extended release, sustained release, etc.)
Pharmacological factors:
I. Gastric Emptying and Gastrointestinal Motility -
Factors that accelerate gastric emptying increases the bioavailability. This is because the drug is
exposed to the larger surface area of the small intestine. .
II There are many gastrointestinal diseases which have an effect on drug absorption-
In case of Crohn’s disease, there is disproportionate absorption of individual components of
cotrimoxazole, increases absorption of sulfamethoxazole, decreases of trimethoprim

38. III Food and Other Substances-
Both rate and extend of absorption of certain antibiotics like rifampicin is reduced after meals.
IV First Pass Metabolism
It means that drug degradation occurs, reducing its bioavailability, when it passed through GIT wall
and then through portal system, before it reaches systemic circulation.
V Drug-Drug Interactions
 Liquid paraffin decreases the bioavailability of fat soluble vitamins as it emulsifies fat.
 Antacids reduces bioavailability of tetracyclines because it forms chelated complex
Miscellaneous Factors
 Area of Absorptive Surface
 State of Circulation at the Site of Absorption (shock, where tissue perfusion decreases) •
 Route of Administration

39. Plasma drug concentration
Time for pea k plasma (blood) concentration
Peak plasma concentration
A rea under- the plasma drug concentraition-time curv,e
(A UC)
Urinary drug excretion
Cumulative amount of drug excreted in 'the urine (Du)
Rate of drug excretion in the urine (dD/dt)
Time for maximum urinary excretion (t)
In vivo pharmacodynamic (PD) comparlson
Maximum pharmacodynamic effect: (Emax> Time for maximum pharmacodynamic effect
Area under- the pharmacodynamic effect-time curve
Onset time for pharmacodynamic effect:
Clinical endpoint study
Limited comparative parallel clinical study using predetermined clinical endpoint:(s) and performed in patients
In vitro studies
Comparative drug dissolution studies
In vitro binding studies
Examples:Cholestyramine resin-In vitro equilibrium and kinetic binding studies
Methods for determination of Bioavailability

40. Urinary drug excretion
1. (dXu/dt)max : The maximum urinary excretion rate, it is obtained
from the peak of plot between rate of excretion versus midpoint
time of urine collection period. It is analogous to the Cmax derived from
plasma level studies since the rate of appearance of drug in the urine is
proportional to its concentration in systemic circulation. Its value increases
as the rate of and/or extent of absorption increases (see Fig.).
2. (tu)max : The time for maximum excretion rate, it is analogous
to the tmax of plasma level data. Its value decreases as the absorption rate
increases.
3. Xu : The cumulative amount of drug excreted in the urine, it
is related to the AUC of plasma level data and increases as the extent of # absorption increases.
The extent of bioavailability is calculated from equations given below:

41. With multipledose study to steady-state, the equationfor computing
bioavailability is:
where (Xu ss) is the amount of drug excreted unchanged during a single
dosing intervalat steady-state.

42. Single dose bioavailability studies are very common, easy, offer less exposure and less tedious. But, it’s
difficult to predict the steady state characteristicsand intersubject variability by this method.
Single dose Vs multiple dose regimens of Bioavailability
Fig: Plasma-time curve profile (Single dose)

43. Multipledose study is difficultto control(poorsubject compliance),exposes the subject to
more drug , highly tedious and time consuming but has several advantageslike:
1. Better evaluation of drug therapeuticeffect in case of longer use.
2. The drug blood levels are higher due to cumulative effect which makes its determination
possible using less sensitive analytical method.
3. Better evaluation of performance of a controlledrelease formulation is possible.
4. Nonlinearityin pharmacokinetics, if present, can be easily detected.
5. Easy to predict the peak & valley characteristicof the drug since the bioavailability is
determined at steady – state.
6. Requires collection of fewer bloodsamples.
7. Can be ethicallyperformed in patientsbecause of the therapeuticbenefit to the patient.
 In multiple dose study, one must ensure that steady state level has been reached. For this, the
drug should be administered for 5-6 elimination half lives before collectingblood sample as well
as a determination of the effect of food on the absorption of the drug from the dosage form.

44. Determination o f AUC and Css,max on multiple dosing upto
steady-state

45. With multiple dose study, the method involves drug administration for at least 5 biological half-lives with a
dosing interval equal to or greater than the biological half-life (i.e. administration of at least 5 doses) to
reach the steady-state. A blood sample should be taken at the end of previous dosing interval and 8 to 10
samples after the administration ofnext dose. The extent of bioavailabilityis given as:
where [AUC] values are area under the plasma level-time curve of one dosing interval in a multiple dosage
regimen, after reaching the steady state and t is the dosing interval.
Bioavailability can also be determined from the peak plasma concentration at steady-state Css max according
to following equation:

46. How does Bioavailabilitydiffers from Bioequivalence?
• If two or more, similardosageforms of the same drug reach the blood circulationat the same
relative rate and extend, those are BIOEQUIVALENT preparationsof thatgeneric drug.
• Difference in bioavailability is usuallyseen with ORAL dosage forms, bioavailability of I.V is
100%, I.M and S.C are assumed to be close to 100%.
• Differences of less than 25% in bioavailabilityamong several formulations of one drug
will usuallyhave no significant effect on clinical outcome, hencesuch formulationscan be called
BIOEQUIALENT.

47. Bioequivalence
It’s commonly observed that there are several formulations of the same drug, in the same dose, in
similar dosage form and meant to be given by the same route. in order to ensure clinical performance
of such drug products, bioequivalencestudies should be performed.
Types of Equivalence:
Chemical Equivalence:
When 2 or more drug productscontain the same labeled chemical substanceas an active ingredient in
the same amount.
PharmaceuticalEquivalence:
When two or more drug productsare identical in strength, quality, purity, content uniformity,
disintegration and dissolution characteristics; they may however differ in excipients. Their plasma
concentration time profiles will be identical without significant statistical difference.

48. TherapeuticEquivalence:
According to the U.S. Food and Drug Administration (FDA), two medicines that have the same
clinical effect and safety profile are said to have therapeuticequivalence. ... For a drug to be
approved as a therapeuticequivalent it must: Be safe and effective. Contain the same active
ingredient as the original medication
Clinical Equivalence:
When the same drug from 2 or more dosage forms gives identical in vivo effects as measured by
pharmacological response or by controlover a symptom or a disease

49. Different methods of studying Bioequivalence
A. In Vivo Bioequivalence study:
a. It requires determination of relative bioavailability after administration of a single dose of test and reference formulations
by the same route, in equal doses, but at different times.
b. The reference product is generally a previously approved product, usually a innovator’s product or some suitable reference
standard.
c. The study is performed in fasting, young, healthy, adult male volunteers to assure homogeneity in the population & to
spare the patients, elderly or pregnant women from rigors of such a clinical investigation.
Types of Design
1.Parallel group design
• In a parallel group design, subjects are divided randomly into groups, each group receiving one treatment randomly.
• Here number of groups is same as number of treatments to be compared.
• Each subject receives only one treatment.
2.Cross over design
• Arrangements in which each subject receives two or more different treatments on successive occasions, are known as
cross over designs.
• In this design, the number of treatments is same as the number of periods.
• This design can be used with any number of treatments, subjects to the restriction that the number of subjects must be a
multiple of the number of treatments.

50. Period refers to the time period in which a study is performed. A two-period study is a study that
is performed on two different days (time periods) separated by a washout period during which
most of the drug is eliminated from the body—generally about 10 elimination half-lives. A
sequence refers to the number of different orders in the treatment groups in a study. For example,
a two-sequence, two-periodstudy would be designed as follows:
where R = reference and T = treatment.

51. Cross Over Design(Detail):
1.Latin Square Cross Over Design: In which
1. Each formulation is administered just once to each subject & once in each study period, &
2. Unlike parallel design, all the subjects do not receive the same formulation at the same time; in a given study
period, they are administered different formulations.
An example of the Latin square cross- over design for a bioequivalence study in human volunteers is given
in following table:-
Examples of Latin-square crossover designs for a bioequivalence study in human volunteers, comparing three
different drug formulations (A, B, C)

52. The same reference and the same test are each given twice to the same subject. Other sequences
are possible. In this design, Reference-to-Referenceand Test-to-Test comparisons may also be
made.
Advantages of Cross overdesign:
 Minimize intersubject variability in plasma drug level.
 Minimize intrasubject variability → affecting bioavailability of a subsequentlyadministered
product.
 Minimize variation due to time effect.
 Make it more possibleto focus more on formulation variables which is the key to success for
any bioequivalencestudy.
Drawbacks of cross-overdesign:-
 Takes long time since appropriatewashout period between 2 administrations is essential.
 Time may be longer if the drug has t1/2 long.
 When the no. of formulationsto be tested are more, the study becomes more difficult and
subject dropout rate may increase.
This can be overcome by use of a balanced incompletedesign in which a subject receives no
more that two formulations.

53. Replicated Cross OverDesign
Replicated crossover designs are used for the determination of individual bioequivalence, to
estimate within-subject variance for both the Test and Reference drug products, and to
provide an estimate of the subject-by-formulation interaction variance. Generally, a four-period,
two-sequence, two-formulationdesign is recommended by the FDA.

54. B. In Vitro Bioequivalence study:
In following circumstances equivalence may be assessed by the use of in vitro dissolution testing:
(B.1) Drugs for which the applicant provide data to substantiate all of the following:
1. Highest dose strength is soluble in 250ml of an aqueous media over the pH range of 1-7.5 at 370C.
2. At least 90% of the administered oral dose is absorbed on mass balance determination or in comparison to an
intravenous reference dose.
3. Speed of dissolution as demonstrated by more than 80% dissolution within 15 minutes at 370C using apparatus
1, at 50 rpm or IP apparatus 2, at 100rpm in a volume of 900 ml or less in each of the following media:
a. 0.1 N hydrochloric acid or artificial gastric juice (without enzymes)
b. A pH 4.5 buffer
c. A pH 6.8 buffer or artificial intestinal juice (without enzyme)
(B.2) Different strength of the drug manufactured by the same manufacturer, where all of the following
criteria are fulfilled:
1. The qualitative composition between the strengths is essentially the same;

55. 2. The ratio of active ingredients and excipients between the strength is essentially the same or in the case of
small strength, the ratio between the excipients is the same;
3. The method of manufacture is essentially the same;
4. An appropriate equivalence study has been performed on at least one of the strength of the formulation
(usually the highest strength unless a lower strength is chosen for reasons of safety); and
5. In case of systemic availability-pharmacokinetics have been shown to be linear over the therapeutic dose
range.
In vitro dissolution testing may also be suitable to confirm unchanged product quality and performance
characteristics with minor formulation or manufacturing changes after approval.
C. Pharmacodynamic studies:
Studies in healthy volunteers of patients using pharmacodynamic parameters may be used for establishing
equivalence between two pharmaceutical products. These studies may become necessary
1. If quantitative analysis of the drug and/or metabolite(s) in plasma or urine cannot be made with sufficient
accuracy and sensitivity.
2. if measurement of drug concentrations cannot be used as surrogate endpoints for the demonstration of
efficacy and safety of the particular pharmaceutical product e.g. topical products without an intended absorption
of the drug into the systemic circulation.

56. D. ComparativeClinicalTrials
It is carried out when
1. The plasma concentrationtime-profile date may not be suitableto assess equivalence
between two formulations.
2. Pharmacodynamic studies cannot be performed because of lack of meaningful
pharmacodynamicparameters, which can be measured.
3. Pharmacodynamic and pharmacokineticstudies are not feasible.

57. Methods:
Single and multiple doses of 5-lg limaprost were orally administered to 12 healthy Chinese subjects. There was a 2-week
washout period between single and multiple dosing. Blood samples were collected at various times.
Limaprost is rapidly absorbed after oral administration and is rapidly eliminated, with no accumulation after multiple
dosing. The drug is well tolerated and no serious adverse events occurred

60. 3.3 Single-dose Pharmacokinetic Parameters
The plasma concentration-timeprofiles of the healthysubjectswho received 5 lg of limaprost are shown in
Fig. 2. The pharmacokineticparametersare shown inTable1. Significantinter-individual variationsin plasma
Concentrationsand pharmacokineticparameterswere foundin the single-dose study.
3.4 Multiple-dosePharmacokineticParameters
The plasma concentration-time profiles of the healthysubjects who received multiple doses of limaprost (5
lg,three times a day for 5 days) are also shown in Fig. 2. The multiple dose pharmacokinetic parameters are
shown inTable 1. The mean values of Cmax, AUC0–t, AUC0–∞, t1/2 and tmax between the single- and multiple-
dosing were no tstatistically different (P[0.05). The accumulation factor R was 0.609 ± 0.432 (R1), indicating that
there was no accumulation after multiple doses of limaprost tablets. There were no statistically significant
differences in either single- and multiple-dose pharmacokinetic parameters between female and male subjects
(P[0.05).