2-(Brian Tomlinson) Pharmacovigilance in Clinical Trials...QT interval prolongation and torsades de...

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PharmacovigilancePharmacovigilance in in Clinical TrialsClinical Trials

Brian TomlinsonProfessor of Medicine and Therapeutics

Division of Clinical PharmacologyDepartment of Medicine & Therapeutics, The Chinese University of Hong Kong,

Hong Kong SAR

Second Annual Symposium on Second Annual Symposium on PharmacovigilancePharmacovigilance, Hong Kong, 4 March 2011, Hong Kong, 4 March 2011

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The traditional drug safety model

Ray A. Nat Rev Drug Discov. 2009; 8(10): 775-9.

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Phase III Clinical Trials

The exposure of a limited number (generally between 500–3000) of patients during clinical development and for a limited timeThe randomized controlled trials may control for disease variability, but generally not for variability in individual response rates or adverse events that are difficult to anticipateMany serious ADRs are infrequent or rare (<1 in 1000 in most cases and occasionally <1 in 10,000) and may not be detected against abackground rate in the population receiving a placebo or active control.To identify an ADR that occurs in one in 10,000 patients, at least 30,000 patients would need to be enrolled in the randomized clinical trial program to have any chance of detecting it.

Amur S et al, CDER, FDA. Personalized Medicine (2010) 7(6), 633–642.

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The challenges of identifying rare adverse drug reactions in clinical trials

Eichler HG et al. Nat Rev Drug Discov. 2008; 7(10): 818-26

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Enhanced pre- and post-marketing safety databases

Most clinical trials are designed and powered to detect differences in primary efficacy end points

e.g. for medications for chronic, non-life-threatening conditions, ICH Technical Requirements recommends sample sizes that might not have adequate power to detect adverse drug reactions (ADRs) occurring in as many as 1 in 100 patients. Although extremely rare ADRs can be practically detected only in a post-marketing setting, using larger pre-marketing safety databases can be beneficial and cost-effective

Ray A. Nat Rev Drug Discov. 2009; 8(10): 775-9.

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Avoidable and unavoidable adverse drug reactions


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Avoidable and Unavoidable ADRs

Off-target binding of the drug could lead to ADRs and may not be related to the same level of exposure that is responsible for on-target efficacy.Unavoidable ADRs are the idiosyncratic reactions for which the underlying mechanisms are not understood -these have been reported to contribute to 10% of ADRs.Unavoidable ADRs may become avoidable after gaining insight into the mechanisms underlying the ADRs, e.g. carbamazepine-induced SJS/TEN and HLA-B*1502, or considered acceptable based upon benefit–risk considerations.


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Toxicities leading to drug withdrawal fromthe US market

Wilke RA et al. Nat Rev Drug Discov. 2007; 6 (11): 904-16.

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US Market Withdrawals (1998-2003)

BronchospasmAnesthesiaRapacuronium19992001

RhabdomyolysisDrug-drug interactions

Cholesterol loweringCerivastatin19972001

Acute liver failureDiabetesTroglitazone19972000

Torsades de PointesDrug-drug interactions

HeartburnCisapride19932000

Ischemic colitis; complications of constipation

Irritable bowel syndrome in womenAlosetron*20002000

Torsades de PointesAntibioticsGrepafloxacin19971999


AntihistamineAstemizole19881999


AntihistamineTerfenadine19851998

Acute liver failureNSAIDBromfenac19971998

Drug-drug interactionsTorsades de Pointes

High blood pressure/Chronic stable anginaMibefradil19971998

RiskUseDrug nameApprovalWithdrawn

Huang SM, Miller M, Toigo T, Chen MC, Sahajwala C, Lesko LJ, Temple R, Evaluation of Drugs in Women: Regulatory Perspective– in Section 11, Drug Metabolism/Clinical Pharmacology (section editor: Schwartz, J), in “Principles of Gender-Specific Medicine”, Ed., Legato M, Academic Press (2004) .

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QT interval prolongation and torsades de pointes


Atrial fibrillation QT interval 420 msec

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Sinus rhythm after a single dose of dofetilideQT interval 560 msec

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Sinus rhythm after a single dose of dofetilideQT interval 560 msec

QT interval > 640 msecfollowed by episode of torsades de pointes

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A Thorough QT Study - TQT

• QTci - QTcorrected individual, exponential

• QTciL - QTcorrected, individual, linear

• QTcF - QTcorrected, Fridericia• QTcB - QTcorrected, Bazett.

Chatterjee DJ et al. J Clin Pharmacol 2009;49(11):1353-1362.

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Genotype-Confirmed Long-QT Syndrome and Normal-Range Corrected QT Intervals

Goldenberg I et al. J Am Coll Cardiol 2011;57:51–9.

Patient with long-QT syndrome type 1 with QTc of 410 ms

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Spontaneous generation of polymorphic ventricular tachycardia

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Treated with nadolol and implantable cardioverter-defibrillator but still had arrhythmic episodes

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Drugs That May Cause Torsade de PointesDrugs commonly involved• Disopyramide• Dofetilide• Ibutilide• Procainamide• Quinidine• Sotalol• BepridilOthers:• Amiodarone• Arsenic trioxide• Cisapride• Calcium-channel blockers: lidoflazine (not marketed in the United States)• Antiinfective agents: clarithromycin, erythromycin, halofantrine, pentamidine,

sparfloxacin• Antiemetic agents: domperidone, droperidol• Antipsychotic agents: chlorpromazine, haloperidol, mesoridazine, thioridazine,

pimozide• Methadone

Roden, DM. N Engl J Med 350:1013, March 4, 2004

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Associations between polymorphisms and drug-induced torsades de pointes


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Drug-induced liver injury

Troglitazone (Rezulin) – thiazolidinedioneDeveloped by Daiichi Sankyo Co.Introduced and manufactured by Parke-DavisAssociated with idiosyncratic hepatitis.Withdrawn in the UK in December 1997Withdrawn in the USA 21 March 2000Withdrawn in Japan soon afterwards

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Selected reports of genetic associations with drug-induced liver injury


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StatinsO

OOH

CH3

CH3

H

HO

CH3

O

CH3 H

O

OOH

CH3

CH3

H

H

OCH3

O

CH3 CH3

CO2-OH

OH

CH3

CH3

HOCH3

O

CH3 H

N CH3

CH3F

CO2-OH

OH

NF

CH3

CH3

O

NH

OH

CO2-OH

N

CH3

CH3

CH3 CH3

OCH3

F

OH

CO2-OH

N

F

OH

CO2-OH

N N

CH3

CH3

OH

OHCO2-

F

NCH3S

CH3

O O

CO2-OH

CH3

S-CoA

lovastatin

pravastatin

simvastatin

fluvastatin

atorvastatin

cerivastatin

pitavastatin rosuvastatin

HMG-CoA

Statins have diverse chemical structures governing binding affinity and lipophilicitybut share the common pharmacophore with resemblance to HMG

Simvastatin and lovastatin are given as lactones and have to be converted to the open acid moiety for enzyme binding

Adapted from Hu M, et al. Current Pharmacogenomics & Personalized Medicine 2009;7:1-26.

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Clinical pharmacokinetics of cerivastatin• Cerivastatin is exclusively cleared via metabolism. No unchanged drug is

excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine. Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route.

• In addition, on the basis of in vitro investigations, there is no evidence for either cerivastatin or its metabolites having any inducing or inhibitory activity on CYP. The apparent lack of any clinically relevant interactions with a variety of drugs commonly used by patients in the target population supports this favourable drug-drug interaction profile.

Muck W. Clin Pharmacokinet 2000;39(2):99-116.

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Cerivastatin

• >90% intestinal absorption• Highly selective to liver• Water-soluble• Rapid hepatic clearance• Metabolites

– M-1 and M-23 (50% and 100% relative potency of cerivastatin)

– excretion: 70% feces, 24% urine

• Linear pharmacokinetics• t½ = 2 - 4 hours

O-Na+HO

OOHFCH3

CH3

H3C

H3C CH3

O N

Data from cerivastatin prescribing information

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Cerivastatin - Clinical Pharmacokinetic Profile

Cerivastatin is a non-complicated drug with respect to bioavailability and biopharmaceutics

Cerivastatin has dual metabolic pathways with the involvement of more than one cytochrome P450 isozyme (CYP 2C8, 3A4)

Cerivastatin has very favourable interaction profile with many common drugs such as digoxin, warfarin, antacids, cimetidine, nifedipine, omeprazole, erythromycin,and itraconozole

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CerivastatinContraindication

• Cerivastatin is contraindicated in patients with hypersensitivity to any component of this medication, in patients with active liver disease or unexplained persistent elevations of serum transaminases, in women during pregnancy, and in nursing mothers. The combined use of cerivastatin and gemfibrozil is contraindicated due to a risk for rhabdomyolysis

Data from cerivastatin prescribing information 1999

In December 1999 Bayer proactively placed the contraindication in the Baycol PI. This was reinforced at the same time by a letter to Health

Care Professionals informing them of this contraindication in the PI. To date, a majority of the cases of rhabdomyolysis reported with cerivastatin

have occurred when used in combination with gemfibrozil.

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Interaction of statins with gemfibrozil

Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil. Alexandridis et al, Am J Med 2000; 109: 261-262.Patient on gemfibrozil and pravastatin 20 mg daily switched to cerivastatin 0.6 mg daily developed rhabdomyolysis

• Predictable since this dose of cerivastatin is equivalentto 4 times that dose of pravastatin and lipophilicityis many times greater (octanol/water ratio 29.5 for cerivastatin, 0.6 for pravastatin)Tomlinson et al, Am J Med 2000; 110: 669-70.

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US-FDA: “... has received reports of 31 U.S. deathsdue to severe rhabdomyolysis associated with use of

Baycol®,12 of which involved concomitant gemfibrozil use...”

EU-EMEA*:” ...480 reports of a sometimes fatal muscle reaction called rhabdomyolysis had been received

globally from patients taking Baycol®..”

http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html*European Medicines Evaluation Agency, Reuters News, August 8-2001

Cerivastatin and Rhabdomyolysis

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Baycol (cerivastatin sodium tablets) Aug 2001Audience: Health Professionals and ConsumersBayer announced the withdrawal of all dosages of its cholesterol-lowering drug with the brand names Baycol/Lipobay (active ingredient: cerivastatin), due to increasing reports of side effects involving muscular weakness (rhabdomyolysis). Fatal rhabdomyolysis associated with Baycol have been reported most frequently when used at higher doses, when used in elderly patients, and particularly, when used in combination with gemfibrozil (LOPID and generics), another lipid lowering drug.[August 08, 2001 - Letter - Bayer]

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Cerivastatin withdrawal

• The problem with cerivastatin was identified by pharmacovigilance by US, European and other agencies

• Better awareness/communication of the data may have identified it earlier

• More detailed Phase I studies might have prevented the problem – older female patients were at greater risk

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CPK Elevations with Cerivastatin 0.8 mg

0

1

2

3

4

5

6

% of Patients

with CPK

>10X ULN

Total *(n=774)

Women > 65 yo(n=90)

Women < 65 yo(n=215)

Men > 65 yo(n=81)

Men < 65 yo(n=386)

Incidence of CPK >10 X ULN in Patients Taking Cerivastatin 0.8 mg

* Of Patients with Elevated CPK: 70% were symptomatic and 80 % discontinued drug

Insull W, et al. J Int Medical Research 2000;28:47-68.

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Gemfibrozil greatly increases cerivastatin plasma concentrations

Backman JT et al. Clin Pharmacol Ther 2002; 72(6):685-691.

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Cerivastatin metabolism pathways

Christians U, et al. Pharmacol Ther 1998;80:1-34.

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SLCO1A2/1B!/1B3/2B1ABCB1/3

ABCB11

ABCG2

ABCB1/C2/G2

ABCC2

SBT

PEPT1

Liver

Gut Kidney

Enterocyte

Hepatocyte

Renalepithelium

Bile ABC1B1

ABCC2/4

OAT4

PEOT1/2

ABCC1/3/6

OCT1-3

OAT1-3

OAT2

OCT1

SLC10A1

ABCC1/3/4

Urine

SLC2B1

Systemic circulation

Portal circulation


Statin distribution, metabolism and elimination

CYP3A4

CYP3A4/5CYP2C8/9/19

?CYP2D6

Skeletalmuscle

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SLCO1A2/1B!/1B3/2B1ABCB1/3

ABCB11

ABCG2

ABCB1/C2/G2

ABCC2

SBT

PEPT1

Liver

Gut Kidney

Enterocyte

Hepatocyte

Renalepithelium

Bile ABC1B1

ABCC2/4

OAT4

PEOT1/2

ABCC1/3/6

OCT1-3

OAT1-3

OAT2

OCT1

SLC10A1

ABCC1/3/4

Urine

SLC2B1


Portal circulation


Cerivastatin and gemfibrozil

CYP3A4

CYP3A4/5CYP2C8/9/19

?CYP2D6

Skeletalmuscle

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Genetic variation associated with statin-induced mytotoxicity


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SLCO1B1 Variants and Statin-Induced Myopathy- a Genomewide Study

The SEARCH Collaborative Group. N Engl J Med 2008; 359: 789-99.

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FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA

FDA News

Simvastatin Used With AmiodaroneAudience: Cardiologic healthcare professionals, pharmacists, other healthcare professionals[Posted 08/08/2008] FDA notified healthcare professionals of the risk of muscle injury, rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This risk is dose-related and increases when a dose of simvastatingreater than 20 mg per day is given with amiodarone. Although a revision of the simvastatin labeling in 2002 described an increased risk of rhabdomyolysis when amiodarone is taken with simvastatin doses greater than 20 mg daily, FDA continues to receive reports of rhabdomyolysis in patients treated concurrently with amiodarone and simvastatin. Prescribers should be aware of the increased risk of rhabdomyolysis when simvastatin is prescribed with amiodarone, and they should avoid doses of simvastatingreater than 20 mg per day in patients taking amiodarone.[August 08, 2008 - Drug Information Page - FDA][August 08, 2008 - Information for Healthcare Professionals - FDA]

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Simvastatin-amiodarone interaction

Ricaurte B, et al. Ann Pharmacother 2006; 40: 753-7

Simvastatin 80 mg /dayAmiodarone 200 mg /day

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Simvastatin

Becquemont L et al. Clin Pharmacol Ther 2007; 81(5):679-684.

Simvastatin-amiodarone interaction

Simvastatin acid AUC(0-24) ↑ by 73% with amiodarone

400mg/day for 3 days

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Nearly complete LD with rs4149056 (521 T>C) in SLCO1B1

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Estimated cumulative risk of myopathy associatedwith taking 80 mg of simvastatin daily, according to SLCO1B1 rs4149056 (*5, 521T>C) genotype. 60% of myopathy cases could be attributed to the C variant

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Simvastatin Simvastatin acid

Pasanen MK, et al., Pharmacogenetics and Genomics 2006, 16:873–879

Open squares --- c.521TT genotype (n=16); solid squares --- c.521TC genotype (n=11); solid triangles --- c.521CC genotype (n=4).

SLCO1B1 521 T>C polymorphism markedly affects the pharmacokinetics of simvastatin acid

Simvastatin acid AUC(0-∞) ↑3.2x in CC vs. TT

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Rosuvastatin dose in Asians

FDA issues rosuvastatin advisory highlighting revised label

March 2, 2005Wilmington, DE - The Food and Drug Administration (FDA) issued a public-health advisory on rosuvastatin (Crestor®) today that highlights a revised package insert for the cholesterol-lowering medication.

Also, based on a pharmacokinetic study that found elevated drug levels in a population of Asian patients, the "Dosage and Administration" section of the label now advises that the 5-mg dose of rosuvastatin be considered the starting dose in this population.

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Associations of ABCG2 421C>A Polymorphism and Pharmacokinetics of Rosuvastatin

Rosuvastatin 20 mg

Chinese subjects Finnish subjects

Open circles: 421CC (n=16); Filled circles: 421CA (n=12);Filled triangles: 421AA (n=4).

Rosuvastatin 20 mg

Zhang A et al., Clin Chim Acta 2006, 373: 99-103. Keskitalo JE, et al. Clin Pharmacol Ther 2009 , 86: 197-203.

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ABCG2 polymorphism increases rosuvastatin plasma levels and efficacy

Tomlinson B, et al., Clin Pharmacol Ther 2010; 87(5): 558-62.

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Hu M, et al. (2009) Current Pharmacogenomics & Personalized Medicine 7:1-26

ABCG2

Liver

HepatocyteBile

ABCC2

ABCB11

ABCB1

ABCC1/3/4

OCT1

OAT2

SLC10A1

SLCO1B1

Portal circulation

Hepatic Uptake and Efflux Transporters Which Influence Statin Pharmacokinetics

ABCG2


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Rosuvastatin – are there interactions with ABCG2 inhibitors?

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Adapted from Nissen SE, et al., N Engl J Med 2007;356:1304-16.

CETP

FC free cholesterol, PL phospholipids, CE cholesteryl ester, LPLlipoprotein lipase,SR-B1Scavenger receptor B1

Metabolism of HDL-C and its role in reverse cholesterol transport

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Cholesteryl ester transfer protein inhibitors

Ranalletta M, et al. J Lipid Res 2010 Epub.

YesYesYesComplex between CETP and HDL

ReversibleReversibleCovalentCETP binding

17 ± 4.813 ± 2.71178 ± 443CE transfer IC50 (nM)

AnacetrapibTorcetrapibDalcetrapib

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ILLUMINATE: Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events

Barter PJ et al, N Engl J Med 2007;357:2109-22.

• Torcetrapib → 72.1% increase in HDL-C, 24.9% decrease in LDL-C• Increased risk of CV events (HR, 1.25; 95% CI, 1.09 to 1.44; P = 0.001)• Increased risk death from any cause (HR, 1.58; 95% CI, 1.14 to 2.19; P = 0.006)• Increase in SBP (5.4 mm Hg), serum Na+, HCO3-, and aldosterone; decrease in K+• Post hoc analyses: increased risk of death with ↓ in K+ or ↑ in HCO3

- > the median

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Putative site of action of torcetrapib on the angiotensin II /aldosterone pathway involving L-type calcium channels

Clerc RG, et al. J Hypertens 2010;28(8):1676-1686.

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A timeline of CETP inhibitors rising

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Cardiovascular outcome studies for diabetes drugs

• US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry; diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December, 2008. http:// www.fda.gov/downloads/Drugs/Guidances/ucm071627 TECOS - sitagliptinSAVOR-TIMI – saxagliptinLEADER – liraglutideEXSCEL – exenatide once weekly

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Conclusions

• Pre-marketing drug safety data is gradually improving• Better understanding of mechanisms of toxicity and

genetic predisposition can facilitate identification of problems an early stage:– QT prolongation– Drug interactions through enzymes and transporters

• Thorough assessment of the clinical pharmacology of new drugs is essential

• Liver toxicity and off-target effects remain a problem• Anecdotal evidence should not be ignored

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If it were not for the great variability among individuals, medicine might as well be a science and not an art.

(1849 – 1919)

Sir William Osler (1892)

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