Clinical Pharmacology and Biopharmaceutics Review

[**NDA** 20-838 se4-015 **Submission Date:** September 27,]{.smallcaps}
2001

[**Drug Name:**]{.smallcaps} Candesartan cilexetil, Atacand®

**[Strength and formulation:]{.smallcaps}** 4 mg, 8 mg, 16 mg and 32 mg
tablets

**[Sponsor:]{.smallcaps}** AstraZeneca

**[Reviewer:]{.smallcaps}** B. Nhi Nguyen, Pharm.D.

**[Type of Submission:]{.smallcaps}** supplemental NDA

**[Background:]{.smallcaps}** Candesartan cilexetil is a pro-drug that
is completely and rapidly metabolized to the active metabolite
candesartan (also known as MI or CV-11974). Candesartan is mainly
eliminated unchanged in the urine and bile. To a minor extent it is
eliminated hepatically to the inactive metabolite MII (also known as
CV-15959). The elimination T ½ is approximately 9-10 hours in healthy
volunteers and slightly longer in hypertensive patients.

Candesartan cilexetil is approved for the treatment of hypertension. For
the original NDA, the sponsor conducted a study in patients with mild to
moderate liver function that did not show a clinically relevant change
in candesartan pharmacokinetics. AUC was 20% higher in patients with
mild to moderate hepatic impairment compared to matched controls. No
accumulation of candesartan was noted. The inactive metabolite, M2, was
not measured.

**[Summary:]{.smallcaps}** This supplemental NDA contains data from
clinical trials, conducted under IND 47,944, that were designed to
investigate the comparative efficacy between candesartan and losartan.
This supplement contains three comparative efficacy studies, one
bioequivalence study and one pharmacokinetic study. The purpose of the
pharmacokinetic study was to compare the pharmacokinetics of candesartan
in mild to moderate hepatic impairment patients (defined by Child Pugh)
to normal controls. The review of the pharmacokinetic and bioequivalence
studies is included in this review.

**Study SH-AHC-0015 -- Bioequivalence study**

Because the comparative efficacy studies used encapsulated losartan for
blinding purposes, the sponsor conducted a bioequivalence study to
ensure that the encapsulation did not affect the pharmacokinetics of
losartan. The pharmacokinetics of a single dose of commercially
available losartan potassium 50 mg was compared to an intact
commercially available losartan potassium tablet that was encapsulated
in a gelatin capsule. The randomized, two-way, crossover study was
conducted in 40 healthy, young subjects.

The encapsulation did not significantly affect the pharmacokinetics of
commercially available losartan. The encapsulated losartan was
bioequivalent to commercially available losartan. The least squares
estimates and 90% confidence intervals were within 0.80-1.25 (See
table).

1.  Least squares estimates and 90% CI for the ratio of treatment
    medians (encapsulated/standard tablet) for losartan and active
    metabolite

  ------------ ------------ --------------- -------------- ---------------
               Losartan                     EXP 3174       

               Estimate     90% CI          Estimate       90% CI

  AUC~0-~      1.00         0.94 -- 1.05    1.02           0.98 -- 1.07

  AUC~0-t~     0.99         0.93 -- 1.05    1.02           0.98 -- 1.07

  Cmax         1.04         0.93 -- 1.17    1.03           0.97 -- 1.10
  ------------ ------------ --------------- -------------- ---------------

The table below shows the similar pharmacokinetics between commercially
available losartan potassium and encapsulated losartan for both losartan
and its active metabolite, EXP 3174.

2.  Losartan and active metabolite pharmacokinetic parameters for both
    formulations

  --------------- ------------- ------------- ------------- -------------
  Parameter       Losartan                    EXP 3174      

                  ET            ST            ET            ST

  AUC~0-~         372 124       374 120       1952 568      1931 629
  (ng\*h/mL)                                                

  AUC~0-t~        354 125       358 120       1923 564      1903 625
  (ng\*h/mL)                                                

  Cmax (ng/mL)    206 108       204 127       248 96        243 94

  Tmax (h)        1.1 0.5       1.1 0.6       3.8 0.6       4.0 1.1

  T ½ (h)         2.1 0.6       2.0 0.5       6.6 0.7       6.3 0.8
  --------------- ------------- ------------- ------------- -------------

Mean SD

ET = encapsulated tablet

ST = standard tablet

**Study SH-AHC-0009 -- Mild to Moderate Hepatic Impairment PK Study**

The sponsor compared the pharmacokinetics from a single dose of
candesartan cilexetil 16 mg in twelve patients with mild (n=6) and
moderate (n=6) hepatic impairment to healthy controls that were matched
for age, gender, and weight. Hepatic impairment was defined by the Child
Pugh criteria. Patients had a statistically significant increase in
candesartan AUC~0-~ of 78 % and Cmax of 65 % compared to volunteers.
(See table below.) Half-life was similar in both groups (approximately 9
hours).

3.  Candesartan PK parameters of hepatic impairment patients and
    volunteers

+--------------+-------------+--------------+-----------------+------+
| *            | **Group**   | **Estimate   | **Estimate (95% | **p  |
| *Parameter** |             | (95% CI)**   | CI)**           | -val |
|              |             |              |                 | ue** |
|              |             |              | **Ratio         |      |
|              |             |              | pati            |      |
|              |             |              | ent:volunteer** |      |
+--------------+-------------+--------------+-----------------+------+
| AUC~0-~      | Patient     | 2021 (1490,  | 1.78 (1.14,     | 0.0  |
| (ng\*h/mL)   |             | 2739)        | 2.78)           | 16\* |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 1135 (900,   |                 |      |
|              | volunteer   | 1430)        |                 |      |
+--------------+-------------+--------------+-----------------+------+
|              |             |              |                 |      |
+--------------+-------------+--------------+-----------------+------+
| Cmax (ng/mL) | Patient     | 156 (116,    | 1.65 (1.04,     | 0.0  |
|              |             | 208)         | 2.61)           | 36\* |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 95 (65, 138) |                 |      |
|              | volunteer   |              |                 |      |
+--------------+-------------+--------------+-----------------+------+

\* statistically significant

Slight insignificant increases in the inactive metabolite AUC~0-t~ and
Cmax were observed in patients but not in volunteers.

Post-hoc analysis of each hepatic impairment group showed that patients
with mild liver impairment had a 30% increase in candesartan AUC~0-~ and
a 56% increase in candesartan Cmax compared to healthy volunteers.
Patients with moderate liver impairment had a 145% increase in
candesartan AUC~0-~ and a 73% increase in candesartan Cmax compared to
healthy volunteers. Only the comparison between moderate hepatic
impairment patients to healthy volunteers was statistically significant.
(See Table below.)

4.  Candesartan PK parameters of hepatic impairment patients and
    volunteers

  --------------- -------------- --------------- ------------------- -------------
  **Parameter**   **Group**      **Estimate (95% **Ratio             **p-value**
                                 CI)**           group:volunteer**   

  AUC~0-~         Mild (CP A)    1730 (1160,     1.30 (0.70, 2.38)   0.324
  (ng\*h/mL)                     2578)                               

                  Healthy        1335 (869,                          
                  volunteer      2051)                               

                                                                     

                  Moderate (CP   2361 (1327,     2.45 (1.16, 5.14)   0.027\*
                  B)             4200)                               

                  Healthy        965 (745, 1250)                     
                  volunteer                                          

                                                                     

  Cmax (ng/mL)    Mild (CP A)    182 (122, 272)  1.56 (0.80, 3.07)   0.150

                  Healthy        117 (57, 237)                       
                  volunteer                                          

                                                                     

                  Moderate (CP   133 (79, 245)   1.73 (0.71, 4.24)   0.174
                  B)                                                 

                  Healthy        77 (48, 122)                        
                  volunteer                                          
  --------------- -------------- --------------- ------------------- -------------

\* statistically significant

CP = Child Pugh

[**Recommendation:**]{.smallcaps} The Office of Clinical Pharmacology
and Biopharmaceutics has completed the review of study SH-AHC-0015 and
study SH-AHC-0009, and recommends the following:

1\. The encapsulated losartan tablet used in clinical trials for
blinding purposes is bioequivalent to the commercially available
losartan tablet.

2\. The Office of Clinical Pharmacology and Biopharmaceutics' agrees
with most of the sponsor's proposed labeling, but also recommends the
following marked labeling changes:

-   **Special Populations**

*Hepatic Insufficiency:* The pharmacokinetics of candesartan were
compared in patients with mild and moderate hepatic impairment to
matched healthy volunteers following a single oral dose of 16 mg
candesartan cilexetil. The increase in AUC for candesartan was 30% in
patients with mild hepatic impairment (Child Pugh A) and 145% in
patients with moderate hepatic impairment (Child Pugh B). The increase
in Cmax for candesartan was 56% in patients with mild hepatic impairment
and 73% in patients with moderate hepatic impairment. The
pharmacokinetics after candesartan cilexetil administration have not
been investigated in patients with severe hepatic impairment. No initial
dosage adjustment is necessary in patients with mild hepatic impairment.
In patients with moderate hepatic impairment, ATACAND should be
initiated at a lower dose (see DOSAGE AND ADMINSTRATION).

-   **PRECAUTIONS**

**Impaired Hepatic Function**

Based on pharmacokinetic data that demonstrate significant increases in
candesartan AUC and Cmax in patients with moderate hepatic impairment, a
lower initial dose should be used for patients with moderate hepatic
impairment. (see DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY,
Special Populations).

-   **DOSAGE AND ADMINISTRATION**

No initial dosage adjustment is necessary for elderly patients, for
patients with mildly impaired renal function, or for patients with
mildly impaired hepatic function (see [CLINICAL
PHARMACOLOGY](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/04000072.htm#K05)
, [Special
Populations](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/04000072.htm#K05S25)
). In patients with moderate hepatic impairment, ATACAND should be
initiated at 8 mg and titrated to response. (See CLINICAL PHARMACOLOGY,
Special Populations).

The optional intra-division briefing was held on May 1, 2002. Patrick
Marroum, Gabriel Robbie, and Krishnan Viswanadhan attended.

> B. Nhi Nguyen, Pharm.D.
>
> Division of Pharmaceutical Evaluation I

FT Initialed by Gabriel Robbie, Ph.D.\_\_\_\_\_\_\_\_\_

CC list: HFD-110: NDA 20-838; HFD-860: (Nguyen, Marroum, Mehta); CDER
Central Document Room

**[Appendix I]{.smallcaps}**

[**Study report:** SH-AHC-0015 Item-Volume-Page: 006-002-019 to
349]{.smallcaps}

**[Title:]{.smallcaps}** A bioequivalence study comparing a single dose
of 50 mg losartan potassium, given either as a commercial Cozaar® tablet
50 mg or as an intact 50 mg Cozaar® tablet (of the same batch)
encapsulated in a gelatin capsule

**[Investigator:]{.smallcaps}** Lars-Goran Nilsson, MD

**[Study center:]{.smallcaps}** Quintiles AB, Phase I Services,
Islandsgatan 2, S-753 18 Uppsala, Sweden

**[Study period:]{.smallcaps}** September 23 -- October 22, 1997

**[Objectives:]{.smallcaps}** To assess the bioequivalence of the
standard commercial losartan tablets compared to the over-encapsulated
losartan tablets that were used for blinding purposes in the comparative
efficacy studies.

**[Design:]{.smallcaps}** open, randomized, single-dose, two-way,
crossover investigation, with a washout period of 6-14 days between the
dose.

**[Population:]{.smallcaps}** Forty healthy adults (27 males, 13
females) completed the study. The demographics are shown in the table
below. All subjects were Caucasian.

5.  Demographics -- Bioavailability study

  ----------------------------- -----------------------------------------
                                **Range (mean SD)**

  Age (years)                   20-33 (24 3)

  Height (cm)                   161-196 (178 8)

  Weight (kg)                   57-90 (74 9)
  ----------------------------- -----------------------------------------

**[Duration:]{.smallcaps}** One day for the treatment (x 2 treatments)
with a 6-14 day washout between treatments

**[Procedure:]{.smallcaps}** Subjects were randomized to one of two
treatments and then crossed over to the other treatment. OTC and
prescription drugs were not allowed one and two weeks, respectively,
prior to dosing and throughout the entire study, with the exception of
paracetamol for occasional severe pain.

### Treatment: The study drug was administered in the morning (\~ 8 am) with 240 mL of room temperature water. It was not mentioned if the patient was in the fasted state.

**[Lot:]{.smallcaps}**

**[Test formulation (ET=encapsulated tablet)]{.smallcaps}**

A commercially available immediate release (IR) losartan 50 mg tablet
(Cozaar®) manufactured by Merck and Co (Batch no HE 303190) was enclosed
in rapidly disintegrating opaque gelatin capsule. The remaining space
was filled with microcrystalline cellulose, without further manipulation
of the marketed tablet by the company Unival, United Kingdom. The
capsules were designated Batch no. H 1164-01-03-01.

**[Reference formulation (ST=standard tablet)]{.smallcaps}**

A commercially available immediate release (IR) losartan 50 mg tablet
(Cozaar®) manufactured

by Merck and Co (Batch no HE 303190) was designated Batch number H
1339-01-01-01 at Astra.

**[Losartan Assay:]{.smallcaps}** Plasma concentrations of losartan and
EXP 3174 were determined by liquid chromatography with fluorescence
detection at Bioanalytical Chemistry, Astra Hassle AB, Molndal, Sweden.
The intra-day CV% is reported for precision. Linearity was defined as a
maximum deviation of 15 % from nominal concentration.

6.  Assay quality

  ---------- ------------ ------------- ----------------- ----------------
             Precision    Accuracy (%)  Sensitivity       Linearity
             (%)                        (ng/mL)           (ng/mL)

  Losartan   CV \< 6.4 %  Within 10 %   4.3               4.3 -- 602

  EXP 3174   CV \< 4.5 %  Within 13 %   1.7               1.7 -- 467
  ---------- ------------ ------------- ----------------- ----------------

**[Pharmacokinetics:]{.smallcaps}** Since losartan and its active
metabolite, EXP 3174 are responsible for the antihypertensive activity,
blood samples for determination of both in plasma were drawn pre-dose
and post-dose for up to 36 hours in each treatment period. Samples were
drawn at the following times: pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2,
3, 4, 6, 8, 10, 12, 18, 24, 30 and 36 hours post dose.

**[Statistics:]{.smallcaps}** The variables AUC and Cmax were analyzed
by ANOVA on a log scale corresponding to the two-way cross-over design
with factors for sequence, period, treatment and subject-within
sequence. The anti-logarithms of the estimates and 90% confidence
intervals for the ratio of the true treatment medians were determined.
Descriptive statistics were calculated for all pharmacokinetic
parameters.

The within-subject standard deviation for ln (AUC) was predicted to be
0.19 and for ln (Cmax) to be 0.25. Thirty-eight subjects would
demonstrate bioequivalence with 90% power for AUC and 70% power for
Cmax. The true mean AUC and Cmax were assumed to differ by at most 10%,
and the significance level was set to 0.05.

**[Pharmacokinetic anaylsis:]{.smallcaps}** Noncompartmental analysis
was performed using WinNonlin version 1.1. Plasma concentrations below
the limit of quantitation were excluded from the pharmacokinetic
evaluations except at time points prior to Cmax, where non-detectable
concentrations were assigned a value of zero.

**[Results:]{.smallcaps}** Forty subjects were randomized and completed
the study. The pharmacokinetic parameters for the two formulations were
similar (see Table below). Plasma levels were measurable for 12 hours
post dose. The descriptive pharmacokinetic parameters are shown in the
table below.

7.  Losartan and metabolite pharmacokinetic parameters for both
    formulations

  --------------- ------------- ------------- ------------- -------------
  Parameter       Losartan                    EXP 3174      

                  ET            ST            ET            ST

  AUC~0-~         372 124       374 120       1952 568      1931 629
  (ng\*h/mL)                                                

  AUC~0-t~        354 125       358 120       1923 564      1903 625
  (ng\*h/mL)                                                

  Cmax (ng/mL)    206 108       204 127       248 96        243 94

  Tmax (h)        1.1 0.5       1.1 0.6       3.8 0.6       4.0 1.1

  T ½ (h)         2.1 0.6       2.0 0.5       6.6 0.7       6.3 0.8
  --------------- ------------- ------------- ------------- -------------

Mean SD

ET = encapsulated tablet

ST = standard tablet

Plasma concentrations of losartan and metabolite are shown in the two
figures below. The standard deviation bar that is going up (T) refers to
the encapsulated tablet, and the standard deviation bar that is going
down () refers to the standard tablet.

1.  Losartan plasma concentrations for both formulations

![](media/image1.jpeg){width="4.074305555555555in"
height="2.584722222222222in"}

2.  EXP 3174 plasma concentrations for both formulations

![](media/image2.jpeg){width="3.7944444444444443in"
height="2.747916666666667in"}

The two formulations were bioequivalent based on the point estimates and
90% confidence intervals for Cmax and AUC.

8.  Least squares estimates and 90% CI for the ratio of treatment
    medians (encapsulated/standard tablet) for losartan and metabolite

  ------------ ------------ --------------- -------------- ---------------
               Losartan                     EXP 3174       

               Estimate     90% CI          Estimate       90% CI

  AUC~0-~      1.00         0.94 -- 1.05    1.02           0.98 -- 1.07

  AUC~0-t~     0.99         0.93 -- 1.05    1.02           0.98 -- 1.07

  Cmax         1.04         0.93 -- 1.17    1.03           0.97 -- 1.10
  ------------ ------------ --------------- -------------- ---------------

**[Reviewer's Comments:]{.smallcaps}** The study was only powered at 70%
for Cmax. However, the within subject standard deviation (0.31) for Cmax
was larger in this study population than that used to calculate 70%
power to detect a difference with respect to Cmax. Thus, the study had
less than 70% power to detect a difference in Cmax.

The within subject standard deviations was 0.15 for ln-transformed
AUC~0-~. Thus, this study population had less variability in AUC than
that used to calculate 90% power to detect a difference in AUC~0-~.

Despite being under-powered to detect a significant difference in Cmax
(yet over-powered to detect a difference in AUC~0-~) between the two
formulations, the sponsor was able to demonstrate bioequivalence between
the two formulations since the 90% confidence intervals for both AUC and
Cmax were within the accepted criteria of 80-125%.

**[Conclusion:]{.smallcaps}** The encapsulated losartan is bioequivalent
to commercially available losartan.

[**Study report:** SH-AHC-0009 Item-Volume-Page: 006-001-016 to
347]{.smallcaps}

**[Title:]{.smallcaps}** Pharmacokinetics of candesartan cilexetil in
patients with moderate to severe impairment of liver function

**[Investigator:]{.smallcaps}** Gertraud Haug-Pihale, MD, PhD

**[Study center:]{.smallcaps}** APEX GmbH, Landsbergerstr, 476, D-81241
Munchen, Germany

**[Study period:]{.smallcaps}** February 13, 1997 to April 30, 1997
(first enrolled / last completed)

**[Objectives:]{.smallcaps}** Given a single candesartan cilexetil 16 mg
dose in patients with moderate to severe liver function, the purposes of
this study were:

-   To document the pharmacokinetics and

-   To evaluate the inactive metabolite (MII) accumulation and
    elimination of candesartan

A secondary objective was to evaluate the safety and tolerability of
candesartan cilexetil.

**[Design:]{.smallcaps}** open-label, single dose

**[Population:]{.smallcaps}** Twelve patients with mild to moderate
liver impairment, defined by the Child Pugh score (CP), and twelve
healthy volunteers matched by age, gender and weight were included in
the study. Six patients had mild liver impairment (CP = A) and six
patients had moderate liver impairment (CP = B).

Participants included Caucasian men (22) and women (2), with a mean SD
age of 56 6 years, weight of 80 17 kg and height of 175 8 cm.

Patients with encephalopathy greater than Grade II or patients with
severe ascites were excluded.

**[Duration:]{.smallcaps}** This was an acute single dose study.

**[Procedure:]{.smallcaps}** Patients were screened and severity of
liver disease was determined according to the Child-Pugh classification
system (see table below). Patients had verified liver cirrhosis by
biopsy or a caffeine clearance 0.8 mL/min/kg. A sonography, aminopyrine
breath test and the indocyanine green test were performed.

9.  Child-Pugh (CP) Score classification

  ------------------ ----------------- ----------------- -----------------
                     **1 point**       **2 points**      **3 points**

  Albumin (g%)       \> 3.5            2.8 -- 3.5        \< 2.8

  Total bilirubin    \< 2.0            2.0 -- 3.0        \> 3.0
  (mg %)                                                 

  Quick-test (PT %)  \> 70             40 - 70           \< 40

  Ascites            No                Moderate          Severe

  Encephalopathy     No                I-II              III-IV
  ------------------ ----------------- ----------------- -----------------

CP A = 5-6 points, CP B = 7-9 points, CP C = 10-15 points

Twelve healthy volunteers matched by age, gender and weight were also
included in the study.

All participants were given one dose of candesartan and blood samples
were drawn at pre-specified times for 36 hours post-dose. Participants
were allowed to leave the clinic after the 24 hour blood draw, but had
to return for the last blood draw at 36 hours post-dose.

### Concomitant medications: Medications considered necessary for the patient could be given at the discretion of the investigator. Drugs not allowed included:

-   Vasodilators or vasoconstrictors (e.g., theophylline, papaverine,
    TCA, neuroleptics)

-   Sympathicomimetics nasal drugs

-   Anti-arrhythmics

-   NSAIDs with the exception of aspirin

-   Chronic use of steroids

-   Immunosuppressives or cytotoxics

-   Potassium supplements

-   Cimetidine

### Treatment: A single dose of candesartan cilexetil 16 mg was administered with 240 mL of water in the morning.

**[Formulation:]{.smallcaps}**

Immediate release candesartan cilexetil tablet 16 mg

Batch no H1191-01-01-01

Manufactured at Astra Production Tablets AB, Sodertalje, Sweden

**[Assay:]{.smallcaps}** Plasma specimens were analyzed for the active
metabolite, candesartan (MI, CV-11974) and the inactive metabolite MII
(CV-15959) using liquid chromatography with fluorescence detection. The
assay quality are shown in the table below for candesartan and M II.

10. Assay quality

  ------------- ------------ ------------- ----------------- ----------------
                Precision    Accuracy (%)  Sensitivity       Linearity
                (%)                        (ng/mL)           (ng/mL)

  Candesartan   CV \< 5.5 %  Within 11 %   0.88              0.88 -- 396

  M II          CV \< 6.1 %  Within 11 %   1.24              1.24 -- 396
  ------------- ------------ ------------- ----------------- ----------------

**[Pharmacokinetics:]{.smallcaps}** Blood samples for determination of
candesartan and MII in plasma were drawn predose and at the following
times post-dose: 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours.

**[Statistics:]{.smallcaps}** All variables were analyzed on a log
scale. For each variable, the mean and a 95% confidence interval were
calculated. The antilogarithms of these results are presented, i.e.,
estimates and confidence limits for the true group median.

Matched pairs were used for comparing the two groups. For each variable
and for each matched pair, the difference in the log values between the
patient and the healthy volunteer was calculated. For each variable, the
mean of all differences was calculated. The differences between patient
and healthy volunteer in all matched pairs and Student's t-distribution
were used for inference.

**[Pharmacokinetic anaylsis:]{.smallcaps}** Non-compartmental analysis
using WinNonlin version 1.1 was used to estimate the usual PK
parameters.

**[Results:]{.smallcaps}** Patients had a statistically significant
increase of 78% in candesartan AUC~0-~ and 64% in candesartan Cmax
compared to volunteers. (See table below.) Half-life was similar in both
groups (approximately 9 hours). Cmax was reached in approximately 4
hours in both groups.

11. Candesartan PK parameters of hepatic impairment patients and
    volunteers

+--------------+-------------+--------------+-----------------+------+
| *            | **Group**   | **Estimate   | **Estimate (95% | **p  |
| *Parameter** |             | (95% CI)**   | CI)**           | -val |
|              |             |              |                 | ue** |
|              |             |              | **Ratio         |      |
|              |             |              | pati            |      |
|              |             |              | ent:volunteer** |      |
+--------------+-------------+--------------+-----------------+------+
| AUC~0-~      | Patient     | 2021 (1490,  | 1.78 (1.14,     | 0.0  |
| (ng\*h/mL)   |             | 2739)        | 2.78)           | 16\* |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 1135 (900,   |                 |      |
|              | volunteer   | 1430)        |                 |      |
+--------------+-------------+--------------+-----------------+------+
|              |             |              |                 |      |
+--------------+-------------+--------------+-----------------+------+
| Cmax (ng/mL) | Patient     | 156 (116,    | 1.65 (1.04,     | 0.0  |
|              |             | 208)         | 2.61)           | 36\* |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 95 (65, 138) |                 |      |
|              | volunteer   |              |                 |      |
+--------------+-------------+--------------+-----------------+------+

\* statistically significant

The candesartan plasma concentration versus time curve is shown in the
figure below.

3.  Candesartan plasma concentrations over time

![](media/image3.jpeg){width="3.973611111111111in"
height="2.8930555555555557in"}

Slight insignificant increases in the inactive metabolite AUC~0-t~ and
Cmax were observed for patients compared to volunteers. (See table
below.) The residual area for MII AUC~0-~ was greater than 20 % for
several patients and volunteers, so the results were not presented.

12. MII PK parameters of hepatic impairment patients and volunteers

+--------------+-------------+--------------+-----------------+------+
| *            | **Group**   | **Estimate   | **Estimate (95% | **p  |
| *Parameter** |             | (95% CI)**   | CI)**           | -val |
|              |             |              |                 | ue** |
|              |             |              | **Ratio         |      |
|              |             |              | pati            |      |
|              |             |              | ent:volunteer** |      |
+--------------+-------------+--------------+-----------------+------+
| AUC~0-t~     | Patient     | 395 (253,    | 1.30 (0.73,     | 0    |
| (ng\*h/mL)   |             | 614)         | 2.28)           | .338 |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 305 (223,    |                 |      |
|              | volunteer   | 417)         |                 |      |
+--------------+-------------+--------------+-----------------+------+
|              |             |              |                 |      |
+--------------+-------------+--------------+-----------------+------+
| Cmax (ng/mL) | Patient     | 18.4 (13.0,  | 1.18 (0.67,     | 0    |
|              |             | 25.8)        | 2.07)           | .536 |
+--------------+-------------+--------------+-----------------+------+
|              | Healthy     | 15.6 (10.4,  |                 |      |
|              | volunteer   | 23.5)        |                 |      |
+--------------+-------------+--------------+-----------------+------+

The MII plasma concentration versus time curve is shown in the figure
below.

4.  MII plasma concentrations over time

![](media/image4.jpeg){width="4.027083333333334in" height="3.03125in"}

The sponsor conducted a post-hoc analysis comparing the hepatic
impairment groups to volunteers. Patients with mild liver impairment had
a 30% increase in candesartan AUC~0-~ and a 56% increase in candesartan
Cmax compared to healthy volunteers. Patients with moderate liver
impairment had a 145% increase in candesartan AUC~0-~ and a 73% increase
in candesartan Cmax compared to healthy volunteers. (See Table below.)

13. Candesartan PK parameters of hepatic impairment patients and
    volunteers

  --------------- -------------- --------------- ------------------- -------------
  **Parameter**   **Group**      **Estimate (95% **Ratio             **p-value**
                                 CI)**           group:volunteer**   

  AUC~0-~         Mild (CP A)    1730 (1160,     1.30 (0.70, 2.38)   0.324
  (ng\*h/mL)                     2578)                               

                  Healthy        1335 (869,                          
                  volunteer      2051)                               

                                                                     

                  Moderate (CP   2361 (1327,     2.45 (1.16, 5.14)   0.027\*
                  B)             4200)                               

                  Healthy        965 (745, 1250)                     
                  volunteer                                          

                                                                     

  Cmax (ng/mL)    Mild (CP A)    182 (122, 272)  1.56 (0.80, 3.07)   0.150

                  Healthy        117 (57, 237)                       
                  volunteer                                          

                                                                     

                  Moderate (CP   133 (79, 245)   1.73 (0.71, 4.24)   0.174
                  B)                                                 

                  Healthy        77 (48, 122)                        
                  volunteer                                          
  --------------- -------------- --------------- ------------------- -------------

\* statistically significant

CP = Child Pugh

[Safety]{.underline}

Patients with impaired liver function reported most of the adverse
events (20 out of 22 reported adverse events). Adverse events that were
attributed to drug included tiredness, dizziness and headache. These
were reported from a total of four participants. The table below shows
the number of participants and reported adverse events.

14. Reported adverse events

  ------------------ ------- ------------------ ------- ----------------- -------
  **Run-in**         **n**   **Dose to 36 h     **n**   **\> 36 hours     **n**
                             post dose**                post-dose**       

  **Patients**                                                            

  Respiratory        2       Fatigue            2       Accident          1
  infection                                                               

  Coughing           1       Bronchitis         1       Bronchitis        1

  Dysphonia          1       Coughing           1       Coughing          1

                             Dizziness          1       Dizziness         1

                             Dysphonia          1       Dysphonia         1

                             Respiratory        1       Erysipelas        1
                             infection                                    

                                                        Leukocytosis      1

                                                        Respiratory       1
                                                        infection         

  **Healthy                                                               
  volunteers**                                                            

                             Headache           1       Dizziness         1
  ------------------ ------- ------------------ ------- ----------------- -------

**[Conclusion:]{.smallcaps}** The sponsor concludes that in patients
with mild liver impairment there is no need for dosage adjustment. In
patients with moderate liver impairment, the dose should be initiated
low and slowly titrated until an antihypertensive effect is achieved.

[**Reviewer's Comments:**]{.smallcaps}

The control group was similar in age, gender and race to the hepatic
impairment patients.

Since the kinetics of candesartan and its metabolite are linear, single
dose should predict multiple doses. Thus, a single dose study for
candesartan is appropriate.

Patients with severe hepatic impairment were not included in this study.

[**Reviewer's Conclusions:**]{.smallcaps} Patients with mild hepatic
impairment do not need the candesartan dose adjusted. Patients with
moderate hepatic impairment should be started on a lower dose of
candesartan, because of the 145% increase in AUC, and slowly titrated to
blood pressure response. The Office of Clinical Pharmacology and
Biopharmaceutics' agrees with most of the sponsor's proposed labeling,
but also recommends the following marked labeling changes:

-   **Special Populations**

*Hepatic Insufficiency:* The pharmacokinetics of candesartan were
compared in patients with mild and moderate hepatic impairment to
matched healthy volunteers following a single oral dose of 16 mg
candesartan cilexetil. The increase in AUC for candesartan was 30% in
patients with mild hepatic impairment (Child Pugh A) and 145% in
patients with moderate hepatic impairment (Child Pugh B). The increase
in Cmax for candesartan was 56% in patients with mild hepatic impairment
and 73% in patients with moderate hepatic impairment. The
pharmacokinetics after candesartan cilexetil administration have not
been investigated in patients with severe hepatic impairment. No initial
dosage adjustment is necessary in patients with mild hepatic impairment.
In patients with moderate hepatic impairment, ATACAND should be
initiated at a lower dose (see DOSAGE AND ADMINSTRATION).

-   **PRECAUTIONS**

**Impaired Hepatic Function**

Based on pharmacokinetic data that demonstrate significant increases in
candesartan AUC and Cmax in patients with moderate hepatic impairment, a
lower initial dose should be used for patients with moderate hepatic
impairment. (see DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY,
Special Populations).

-   **DOSAGE AND ADMINISTRATION**

No initial dosage adjustment is necessary for elderly patients, for
patients with mildly impaired renal function, or for patients with
mildly impaired hepatic function (see [CLINICAL
PHARMACOLOGY](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/04000072.htm#K05)
, [Special
Populations](../../../../../../../../pdr/static.htm%3Fpath=pdrel/pdr/04000072.htm#K05S25)
). In patients with moderate hepatic impairment, ATACAND should be
initiated at 8 mg and titrated to response. (See CLINICAL PHARMACOLOGY,
Special Populations).

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