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Pharmacokinetic approaches to treatment of drug addiction Expert Rev. Clin. Pharmacol. 1(2), 277–290 (2008)

David A Gorelick Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA Tel.: +1 443 631 8004 Fax: +1 443 631 8037 [email protected]

The pharmacokinetic approach to treatment targets the drug molecules themselves, aiming to reduce their concentration at the site of action, thereby reducing or preventing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Early clinical trials with anticocaine and antinicotine vaccines have shown reduced drug use and good tolerability. Also showing promise in animal studies are monoclonal antibodies against cocaine, methamphetamine and phencyclidine, as well as the enhancment of cocaine metabolism with genetic variants of human butyrylcholinesterase, using a bacterial esterase or catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient compliance, absence of medication interactions and benefit for patients who cannot take standard medications. KEYWORDS: bacterial esterase • butyrylcholinesterase • cocaine • drug addiction • methamphetamine • monoclonal antibody • nicotine • pharmacokinetics • phencyclidine • vaccine

Conventional (pharmacodynamic) pharmacological treatment for drug addiction targets the body, that is, it aims to modulate or disrupt the action of the drug on its sites of action in the body. This pharmacodynamic treatment approach has not yielded broadly effective medications for many drugs of abuse. This failure may be due to several factors, including an incomplete understanding of the neuropharmacological mechanisms mediating the psychoactive actions of the abused drug (e.g., when a drug acts on several different neurotransmitter systems) or a lack of therapeutic compounds that have the appropriate safety and pharmacokinetic properties for clinical use. In view of these limitations of the pharmacodynamic treatment approach, there has been growing interest in a pharmacokinetic treatment approach that targets the drug molecule itself. As the name implies, this approach aims to maintain the abused drug below its minimally effective concentration at its sites of action, rather than modulating or disrupting the drug’s pharmacodynamic action. This effect might be useful in two clinical contexts. First, acutely reducing (free) drug concentration after drug intake might reduce or prevent consequences from acute drug toxicity or overdose (a clinical problem www.future-drugs.com

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for all drugs except nicotine). Second, longterm prevention of effective concentrations at the site of action in the brain might keep the drug-addicted (dependent) patient from experiencing any reinforcing effects from drug taking, neither the positive reinforcement of the ‘high’ nor the negative reinforcement of relief of withdrawal symptoms. This might, over time, lead to extinction of drug-seeking and drug-taking behavior. It might also reduce the chance of relapse in abstinent patients by blocking the priming effect of a single drug dose (i.e., reducing the likelihood of a lapse becoming a relapse) [1]. In both clinical contexts, a key factor in treatment success is the generation of sufficient pharmacokinetic capacity to substantially reduce free drug concentrations at the site of action, regardless of the total body burden of drug. The degree of reduction in free drug concentration that is needed will vary with the pharmacodynamic action of the drug. Binding of all drug molecules (i.e., zero free drug or zero receptor occupancy) is not required to abolish pharmacodynamic effects. In addition, just slowing the rate of drug entry into the brain and of receptor binding may be of therapeutic benefit because the reinforcing subjective effects of drugs are positively correlated with these rates [2]. In the context of long-term

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addiction treatment, a second factor is having sufficient pharmacokinetic capacity to prevent rapid drug distribution into the brain after intravenous or smoked drug intake and to make it impractical for the patient to increase their drug intake enough to overcome the treatment effect. This does not require that it be theoretically impossible to do so but merely that the amount of drug required be unlikely to be available and accessible to the patient. In this regard, the pharmacokinetic approach can be considered analogous to the pharmacodynamic approach of receptor blockade. 100% receptor blockade (i.e., 0% receptor availability) is not necessarily required for successful treatment, as long as the degree of blockade is impractical for the patient to overcome with increased drug use. The pharmacokinetic approach has two theoretical advantages over the pharmacodynamic approach [3]. First, no knowledge is needed of the mechanism of action of the drug. Second, since the treatment targets only the molecules of the abused drug (rather than the brain), it should have no drug–drug interactions and no direct pharmacodynamic actions (although other effects of the treatment are possible), thus minimizing side-effects. This makes pharmacokinetic treatment especially attractive for patients already taking other medications or those who should avoid taking conventional medications (e.g., pregnant women or those with severe medical or psychiatric comorbidity). However, the pharmacokinetic approach may have disadvantages. First, its therapeutic specificity means that the patient may switch to another drug that is not affected by the treatment, either from the same pharmacological class (e.g., a patient abusing stimulants switching from cocaine to amphetamines) or a different pharmacological class. In patients using multiple drugs, which is common, successful cessation of use of the targeted drug may leave other drug use unchanged or even increased in compensation. In principle, this could be addressed by developing antibodies that bind to more than one drug or by administering a combination of different antidrug antibodies. Second, the treatment will not reduce drug craving or withdrawal symptoms, thus leaving the patient at continued risk for drug abuse. To the extent that peripheral drug binding rapidly reduces brain concentrations of free drug, pharmacokinetic treatment might even precipitate or worsen a withdrawal syndrome. In theory, attempts to selfmedicate craving or withdrawal by trying to overcome the treatment effect could result in increased drug use. Third, pharmacokinetic treatment provides no intrinsic reinforcement of its own, unlike agonist treatments, such as methadone for opioid addiction. This may make it difficult to motivate patients for treatment, similar to the difficulties in motivating patients for opioid receptor antagonist treatment with naltrexone. Therefore, pharmacokinetic treatment is best delivered in the context of psychosocial treatment that enhances motivation for treatment and addresses the underlying psychological and behavioral issues of addiction.

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Therapeutic approaches

Two major pharmacokinetic treatment approaches are currently in active development: ‘peripheral blocker’ and increased drug metabolism (BOX 1). Peripheral blocker

The peripheral blocker approach aims to bind the drug of abuse in circulation, reducing the concentration of free (unbound) drug available to exert pharmacodynamic effects. The complexes formed are too large to cross the blood–brain barrier, thus keeping drug out of the brain. This is accomplished with drug-specific antibodies, either generated in vivo by an induced active immune response (active immunity or antidrug vaccine) or by administering antibodies created outside the body (passive immunity). The ability to successfully achieve this goal depends on several characteristics of the antibody: • Intrinsic affinity for the drug: affinity should be high enough to substantially reduce the amount of free drug in circulation. Theoretical calculations suggest that an IgG antibody with an affinity of 40 µM at a concentration of 40 µg/ml would bind approximately two-thirds of circulating cocaine molecules [4]; • Specificity of drug binding: the ideal antidrug antibody should not bind structurally similar endogenous compounds (e.g., neurotransmitters), to avoid interfering with normal physiological function or treatment medications that might be administered concurrently. Binding of (inactive) drug metabolites is also a disadvantage because it occupies binding sites that become unavailable for active drug. However, this might be advantageous for drugs with active metabolites, such as methamphetamine and its active metabolite amphetamine; • Speed of drug binding: smoked and intravenously injected drugs reach the brain in seconds and exert psychological and physiological effects within minutes. Antibody binding of drug should be extremely rapid to prevent brain entry. Studies of antibodies in model systems suggest that binding of small molecules occurs in seconds, making it plausible that antidrug antibodies would be effective in vivo [4]. Box 1. Pharmacokinetic approaches to treatment of drug addiction. Peripheral blockers • Active immunity (antidrug vaccine) • Passive immunity (monoclonal antibody)

Increased drug metabolism • Enzymes: – Butyrylcholinesterase – genetically improved – Bacterial esterase • Catalytic monoclonal antibody

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Pharmacokinetic approaches to treatment of drug addiction

A second possible mechanism for peripheral blockers is slowing of drug clearance from the body. This may be relevant for the treatment of nicotine (tobacco) addiction. Antinicotine antibodies significantly decrease nicotine clearance in rats and prolong its terminal half-life [5]. Human cigarette smokers who are genetically slow nicotine metabolizers smoke fewer cigarettes daily, inhale less smoke [6] and may be more successful at smoking cessation [7] than those who are faster metabolizers, suggesting that antibody-induced slowing of nicotine metabolism may provide therapeutic benefit. An important safety issue for peripheral blockers is that the antibody–drug complexes are nontoxic, especially to the kidneys. Increased drug metabolism

This approach aims to increase drug metabolism so that an insufficient concentration of drug is reached at the site of action. This is accomplished with either catalytic monoclonal antibodies (mAbs) or enzymes that metabolize the drug. Both human and bacterial enzymes have been used, either in their natural state (wild-type) or genetically engineered with enhanced catalytic properties. In addition to issues of affinity, specificity and speed of activity, catalytic treatments raise the theoretical possibility of production of pharmacologically active drug metabolites with undesirable actions. This is not a practical issue for cocaine (the only drug for which catalytic treatments are currently being developed) since it is catalyzed into inactive metabolites. Advantages & disadvantages

Each pharmacokinetic treatment approach has its own advantages and disadvantages (TABLE 1). Antidrug vaccines generate active immunity so that antidrug antibodies persist for months after vaccination. This offers substantial patient compliance advantages over treatments that must be taken daily. However, active immunization (vaccination) generates a highly variable antibody response (with substantial individual differences) that takes weeks to months to fully develop, leaving patients

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vulnerable in the interim. Another disadvantage is that vaccines may not be effective in patients with impaired immune systems, such as those with HIV infection. Treatment with exogenous antibodies (passive immunity) or a drug-metabolizing agent takes effect immediately, does not require an active immune response by the patient and allows precise control of the characteristics and dose of administered agent. Disadvantages include shorter duration of action (hours to days), the need for large doses (thus requiring large-scale, efficient manufacture to keep costs affordable) and possible antigenicity of the therapeutic agent (which may trigger unwanted immune reactions in patients). A catalytic mechanism of action allows one molecule of a therapeutic agent to inactivate (break down) multiple drug molecules. By contrast, each molecule of a passive binding agent (e.g., mAb) can inactivate (bind) only one drug molecule per binding site. Thus, passive binding agents, unlike catalytic agents, in theory might have to be administered in doses achieving mole equivalence between binding sites and drug molecules, potentially requiring very large doses of the therapeutic agent; however, animal studies with antimethamphetamine and antinicotine antibodies suggest that mole equivalence is not necessarily required for therapeutic effect. Furthermore, additional drug intake might saturate the binding sites, resulting in no further therapeutic effect. A potential disadvantage of enhancing drug metabolism is the generation of drug metabolites that may themselves have undesirable pharmacological activity. This is not a practical issue for cocaine, which generates inactive metabolites. A combination of treatments may be most effective, such as initial treatment with a passive immunity or an enzymatic agent until an antidrug vaccine has generated active immunity. The pattern of treatment advantages and disadvantages suggests that antidrug vaccines may be most useful for prevention or long-term treatment of drug addiction, while passive immunity or enzymatic approaches may be most useful for treatment of acute drug toxicity or overdose. This article reviews the current state of development of each approach.

Table 1. Key characteristics of pharmacokinetic treatments for drug addiction. Characteristic

Peripheral blocker (antibody)

Increased drug metabolism

Active immunity

Passive immunity

Enzyme

Catalytic antibody

Onset of action

Weeks to months

Immediate

Immediate

Immediate

Duration of action

Months

Days

Days

Days

Specificity of action

Very high

Very high

High

Very high

Control over treatment agent

Low

High

High

High

Possibility of saturating binding sites

Medium

Medium

Low

Low

Likely clinical use

Addiction

Toxicity/overdose

Toxicity/overdose

Toxicity/overdose

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Antidrug vaccines

Molecules of abused drugs are too small (generally a few hundred daltons) to generate an immune response by themselves. The drug molecule must be made antigenic by coupling to a larger molecule. Antidrug vaccines are currently in clinical trials for cocaine and nicotine dependence (TABLE 2). Vaccines for methamphetamine, phencyclidine (PCP) and heroin/morphine have shown promise in animal studies. Anticocaine vaccine

The anticocaine vaccine was created by conjugating succinylnorcocaine to a nontoxic subunit of recombinant cholera toxin B, administered with aluminum hydroxide adjuvant (TA-CD, originally developed by Xenova, now owned by Celtic Pharmaceutical, Hamilton, Bermuda). In a Phase I clinical trial, 34 abstinent cocaine-dependent subjects received three intramuscular injections over 2 months, of either 13, 82, 709 µg or placebo [8]. Anticocaine antibodies (primarily IgG) were detectable 2 weeks after the second injection, peaked at 3 months and were undetectable at 1 year. Antibody levels were positively correlated with vaccine dose and number of injections. Antibodies were specific for cocaine, with little cross-reactivity with benzoylecgonine and none with lidocaine. In a Phase IIa, open-label, clinical trial, 18 cocaine-dependent outpatients received either four 100-µg injections over 8 weeks or five 400-µg injections over 12 weeks [9]. Cocaine-specific antibodies were detectable at 4 weeks, peaked at 10 or 12 weeks, respectively, were still detectable at 6 months and undetectable at 1 year. Subjects receiving a 2000-µg total dose had a significantly higher mean antibody titer response than subjects receiving a 400-µg total dose, but there was wide variation in individual response. The eight subjects who received a booster vaccination at 9–12 months all had increased antibody levels 1 month later. The Phase IIa open-label trial provided some evidence of efficacy. Subjects receiving the higher vaccine dose (2000 µg) were more likely than those receiving the lower dose (400 µg) to have cocaine-free urine samples (collected three-times weekly during the 12-week treatment period) and less likely to have relapsed (43 vs 89%) at the 6-month follow-up. All

subjects who used cocaine during the active treatment period reported attenuation of the acute euphoric effects of cocaine, as did two-thirds of subjects at the 6-month follow-up. A Phase IIb, controlled, clinical trial of this vaccine was recently completed in 114 cocaine- and opioid-dependent (on methadone maintenance treatment) subjects randomly assigned to receive five injections (double-blind) over 12 weeks of either active or placebo vaccine, with 8 weeks of postvaccination follow-up [10]. The vaccine was well tolerated, with 96% of subjects receiving all five vaccinations. The maximum mean antibody response occurred at 4 weeks and persisted for at least 12 weeks. Approximately three-quarters of vaccinated subjects had an effective antibody response. In preliminary statistical analyses, there was a correlation between higher antibody titers and lower cocaine use. The vaccine group had significantly less cocaine use (measured by threetimes weekly urine drug testing) than the placebo group during the first 10 weeks of treatment. A 50% or greater reduction in cocaine use from baseline occurred in 28% of subjects receiving vaccine and 15% of subjects receiving placebo. The vaccine effect was significant in male subjects (two-thirds of subjects) but not in female subjects [11], possibly because female subjects receiving placebo also showed a significant decrease in cocaine use during the treatment period, while male subjects receiving placebo did not. There was no significant vaccine treatment effect (in the total sample) during the post-treatment follow-up phase [10]. The fading of treatment response was apparently due to increased cocaine use by the vaccine group during the second 10 weeks, while cocaine use by the placebo group remained unchanged. This finding suggests that persistently high antibody titers are needed to maintain a treatment effect, perhaps requiring multiple vaccinations. A booster vaccination administered after 6 months to 35 subjects in this study was well tolerated and resulted in a substantial rise in antibody titer [10]. In a complementary Phase II human laboratory study, ten nontreatment-seeking cocaine-dependent men received a vaccine dose (82 or 360 µg) at 1, 3, 5 and 9 weeks [12]. Cocainespecific antibody levels peaked at 13 weeks, with a sevenfold range across subjects and were negligible or undetected at 1 year. Subjects received a laboratory challenge of smoked cocaine (0, 25 or 50 mg) before the first vaccination and

Table 2. Antidrug vaccines in clinical development. TA-CD

NicQb

NicVAX®

TA-NIC

Target drug

Cocaine

Nicotine

Nicotine

Nicotine

Hapten

Succinylnorcocaine

Nicotine

3’-aminomethyl-nicotine

Nicotine butyric acid

Carrier protein

Cholera toxin B subunit

Qb bacteriophage virus protein coat

Pseudomonas aeruginosa Cholera toxin B subunit exoprotein A

Company

Celtic

Cytos *

Nabi

Celtic

*

Licensed to Novartis.

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weekly thereafter for 13 weeks. Compared with the prevaccination response, there was a significant decrease at week 13 in the positive subjective response to both the 25(45–55%) and 50-mg (35–42%) cocaine doses. Among the five subjects with the highest antibody levels, there was a 79% decrease between week 3 and week 13 in ‘good drug effect’ from the 25-mg dose and a 49% decrease from the 50-mg dose. These five subjects had a more than 50% decrease in selfreported cocaine use between weeks 3 and 13, while the other five subjects reported no decrease in cocaine use. There was no evidence of a compensatory increase in cocaine use in order to overcome the antibody effects. Four subjects had brain PET imaging with 11C-cocaine at baseline and after vaccination at week 13 [13]. Mean occupancy of biogenic amine presynaptic transporters by cocaine was 59% (range: 37–71%) at baseline and 48% (range: 25–70%) at week 13. One subject showed increased occupancy over the interval. Antinicotine vaccines

Three antinicotine vaccines are currently in clinical development (TABLE 2). NicQb

The CYT-002–NicQb or nicotine-Qb vaccine (Cytos Biotechnology, Zurich, Switzerland; recently licensed to Novartis) uses nicotine covalently bonded to virus-like particles formed from the protein coat of the Qb bacteriophage virus [14,15]. Each particle exposes approximately 585 nicotine molecules, making them highly antigenic. In animal studies, the antibody is highly specific for nicotine, with negligible cross-activity with cotinine (a major nicotine metabolite) or acetylcholine [15]. In a Phase I clinical trial in 32 healthy nonsmokers, all subjects developed high-affinity, nicotine-specific IgM antibodies within 7 days and IgG antibodies within 2 weeks [15]. Antibody titers were increased by a second vaccination 4 weeks later, with peak levels at 5–8 weeks. Use of an aluminum hydroxide (alum) adjuvant also increased the antibody response. The estimated antibody half-life was 7–10 weeks. In a recent Phase II, multisite, controlled clinical trial, 341 smokers willing to quit received five monthly injections of active vaccine (100 µg) with alum adjuvant (n = 229) or adjuvant alone (n = 112) over 4 months [14]. All subjects received individual smoking cessation counselling for 3 months beginning 1 month after the first vaccination, which was also the target quit date. The efficacy analysis included only the 239 subjects (159 active vaccine and 80 placebo) who did not use nicotine-replacement therapy during the study. There was no significant difference in continuous smoking abstinence (assessed by self-report and expired breath CO levels) at 6 months between the active and placebo vaccine groups (28 vs 21%) [16]. However, there was wide individual variability in antibody response and a significant positive correlation between antibody titer and abstinence rate. When subjects were divided into tertiles based on antibody titers, subjects in the

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high-antibody group were significantly more likely than those in the medium-, low-antibody groups or placebo group to have achieved continuous abstinence at 6 months (57 vs 32, 32 and 31%, respectively) and at 12 months (42 vs 21, 26 and 21%, respectively). Total cigarette consumption in the high-antibody group was less than half of that in the placebo group. There was no evidence of a compensatory increase in smoking by vaccinated subjects who did not achieve abstinence. The investigators estimated that a threefold increase in antibody titers would have brought 79% of subjects into the high-antibody group. NicVAX®

The NicVAX® vaccine (Nabi Biopharmaceuticals, Rockville, MD, USA) uses 3´-aminomethyl-nicotine coupled to Pseudomonas aeruginosa exoprotein A. In a Phase IIa, multicenter, controlled clinical trial, 68 smokers received doses of 200, 100 or 50 µg or placebo four times over 26 weeks (0, 4, 8 and 26 weeks) and were monitored for an additional 12 weeks [17]. No antibody was detected until after the second vaccination. There was a positive dose–response relationship between vaccine dose and antibody level, with wide individual variability. Subjects receiving 200-µg doses of vaccine were significantly more likely than the other groups to achieve 30 days of continuous abstinence (expired breath CO ≤ 8 ppm; 38 vs 7, 0 and 9%, respectively) and achieved abstinence in a shorter interval. There was no evidence of compensatory increases in smoking or precipitation of nicotine withdrawal. In a Phase IIb, controlled clinical trial, 301 smokers (≥15 cigarettes daily) received one of two vaccine doses (200 or 400 µg; n = 201) or placebo (n = 100) five times over 6 months, with the target quit date 1 week after the second vaccination [18]. The group receiving the highest vaccine dose had the best results, with a quit rate of 25% after 8 weeks (vs 13% for the placebo group) and 16% after 1 year (vs 14% for the 200-µg group and 6% for the placebo group). There was a direct correlation between antibody titers and quit rates. At 6 months, the 61 subjects with the greatest antibody response had a significantly higher rate of 8-week continuous abstinence than subjects receiving placebo (24.6 vs 13%) [101]. These subjects had a 9month continuous abstinence rate of 20 vs 6% for placebo. The group of high antibody responders also smoked significantly fewer cigarettes during the study than the placebo group. Their median number of cigarettes smoked per day declined from 20 at baseline to ten during the study. Subjects with lower antibody responses did not differ from the placebo group in any smoking measure. There was no evidence of a compensatory increase in smoking or increase in withdrawal symptoms. Rat studies with this vaccine provide data relevant to potential clinical use. Chronic administration of nicotine (20 intravenous injections daily or continuous subcutaneous release from an osmotic minipump) during an 11-week period of vaccination did not alter the titers of antinicotine antibodies or the 50% reduction in nicotine distribution into the brain caused by vaccination [19]. Vaccination of pregnant rats had no adverse

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effects on the fetus and reduced nicotine distribution into fetal brain by up to half, comparable with reductions in maternal brain [5,20]. TA-NIC

The TA-NIC vaccine (originally developed by Xenova, now owned by Celtic Pharmaceutical, Hamilton, Bermuda) uses nicotine butyric acid covalently linked to a nontoxic subunit of recombinant cholera toxin B. Little clinical data are publicly available. In a Phase I/II clinical trial, 60 subjects received six injections over 12 weeks of either active vaccine or placebo [21]. Peak antibody levels were reached at around 15 weeks. At 12 months, subjects receiving the higher vaccine doses (1000 or 250 µg) had a higher point prevalence of abstinence than subjects receiving placebo (38 and 19 vs 8%). Anticotinine vaccine

As an alternative approach to antinicotine vaccines, an anticotinine vaccine has been developed by coupling 4-thio-cotinine to tetanus toxoid [22]. Cotinine is a major nicotine metabolite that may counteract nicotine’s actions in the brain. To the extent that this occurs, reducing brain cotinine levels might result in decreased smoking (nicotine intake) and improved response to nicotine-replacement therapy. Vaccination of rats increased serum cotinine levels after nicotine administration (presumably because of peripheral binding) without altering nicotine levels. Safety

The anticocaine and antinicotine vaccines have been well tolerated. The most common adverse events were transient (1–3 days) local reactions at the injection site, such as pain, tenderness, edema, rash, erythema and itching, in up to 90% of subjects [8,9,14,15,17]. Up to a third of subjects have had transient, mild influenza-like symptoms (headache, nausea, malaise and fever), usually resolving within 24 h [8,14,15,17]. The only reported serious adverse events (nature not specified) occurred in the Phase II trial of the Nic-Qb vaccine: five in the vaccine group and three in the placebo group [14]. One subject in the Phase IIb trial of the NicVAX vaccine had an allergic anaphylactic reaction that resolved with medication [18]. Other antidrug vaccines

Vaccines against methamphetamine and heroin/morphine have been studied in animals. An antimethamphetamine vaccine was created by coupling to blue carrier hemocyanin protein or to bovine serum albumin [23]. When administered to mice along with Freund’s adjuvant, the vaccine elicited substantial antimethamphetamine antibody titers. Vaccine pretreatment significantly reduced (by 20–25%) the increased locomotor activity produced by methamphetamine (0.5 or 1.0 mg/kg intraperitoneally). A second antimethamphetamine vaccine was created by coupling to keyhole limpet hemocyanin [24]. Rats immunized with the vaccine three

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times over 6 weeks developed substantial serum titers of antimethamphetamine antibodies, but no change in their locomotor response to a methamphetamine challenge. Antibody titer and affinity were not altered by twice-weekly injections of methamphetamine throughout the 8-week study period, suggesting that drug exposure did not interfere with the immune response. The heroin/morphine vaccine was created by coupling morphine hemisuccinate to the recombinant nontoxic polypeptide H chain of tetanus toxin [25]. In rats, the vaccine elicited specific antiheroin/morphine antibodies, which did not crossreact with endogenous opioids (leu-enkephalin and β-endorphin) or opioid medications (methadone, naltrexone and buprenorphine). Vaccination substantially prevented the reinstatement of heroin self-administration in previously trained rats. Immunized animals did not show a compensatory increase in self-administration. Route of administration

Conventional vaccines require intramuscular administration, which may raise two barriers to their use in drug-abuse treatment. First, some patients may object to injection with a needle, reducing treatment acceptance. Second, intramuscular administration requires a licensed clinician (physician or nurse). Many drug-abuse treatment programs have limited availability of such staff because of financial or other constraints. A noninjection route of administration for an antidrug vaccine might overcome these barriers. Two approaches to noninjection vaccine administration are currently in development. Nabi Biopharmaceuticals is collaborating with Aktiv-Dry (Boulder, CO, USA) to reformulate its NicVAX antinicotine vaccine into particles 1–3 µm in diameter that form a stable, dry powder suitable for inhalation [102]. The partners have received National Institute on Drug Abuse funding for Phase I and II development. Lyfjathroun Biopharmaceuticals (Reykjavik, Iceland) has developed a mucosal adjuvant that allows effective intranasal vaccine administration [26]. Macrogol-6-glycerol capylocaprate (RhinoVax) is a mixture of mono and diglycerides of caprylic and capric acids, with all free alcohol groups pegylated. When used in conjunction with an anticocaine vaccine (cocaine conjugated to keyhole limpet hemocyanin), two doses of intranasal vaccine generated specific anticocaine antibodies in mice, albeit at a fivefold lower serum level than after subcutaneous vaccination. Both vaccination routes comparably inhibited cocaine distribution into the brain after intranasal or intraperitoneal cocaine administration. Passive antidrug immunity

The goal of the passive immunity approach, as with that of the active immunity (vaccine) approach, is to administer an agent that will bind enough drug molecules to keep drug levels below their minimally effective concentration at the site of action. Early studies used a heterogenous mixture of polyclonal

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antibodies extracted from the blood of immunized animals. Current work uses mAbs produced by a single cloned antibody-producing cell extracted from an immunized animal (usually mice). mAbs are homogenous, can be selected and engineered for high affinity and specificity and can be chimerically humanized to minimize antigenicity [27]. Duration of action is determined somewhat by the structure of the antibody administered [27]. A complete IgG antibody molecule (~150,000 Da) has a half-life in blood of approximately 3 weeks. The antigen-binding fragment (Fab) (∼50,000 Da) and single chain antigen-binding fragment (variable regions of both light and heavy antibody chains fused into one protein; scFv; ~27,000 Da) have half-lives of less than a day because of rapid clearance by renal glomerular filtration. Hapten design is being used to develop mAbs with high affinity for a group of structurally related drugs, such as amphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) [28], thus overcoming one of the potential drawbacks of high specificity. No antidrug mAb has been in clinical trials but high-affinity mAbs against cocaine, PCP, methamphetamine and nicotine are in active preclinical development. Murine anticocaine mAbs, such as 2E2 and GNC92H2, have shown in vivo efficacy in reducing cocaine self-administration [29] and reinstatement of self-administration after extinction in rats [30]. Acute administration of GNC92H2 mAb protects mice from the acute toxicity (seizures and death) of high-dose intravenous cocaine, even when administered 3 min after the cocaine [31]. Treatment with GNC92H2 mAb significantly reduced the increased cocaine self-administration associated with free access to cocaine after anticocaine vaccination (cocaine coupled to keyhole limpet hemocyanin), extinction and reinstatement (relapse) [29], suggesting that combining active and passive immunity might be a promising clinical approach. The 2E2 mAb has high affinity for cocaine (KD = 4 nM) and its active metabolites norcocaine and cocaethylene (formed from cocaine and ethanol) and much less affinity for inactive metabolites, such as benzoylecgonine, ecgonine methylester and ecgonine [32]. Humanized 2E2 (with a human γ-heavy chain) in equimolar doses to injected cocaine substantially increases the plasma concentration and decreases the brain concentration and volume of distribution of cocaine, without altering cocaine clearance from the body [33]. A single intravenous infusion of 2E2 (120 mg/kg or 0.8 µmol/kg) significantly increased, for up to a week, the dose of cocaine needed to prime reinstatement of cocaine self-administration (an animal model of relapse) [30]. High-affinity mAbs against methamphetamine and PCP are being commercialized by InterveXion Therapeutics (Little Rock, AR, USA). The high affinity (KD = 11 nM) antimethamphetamine mAb mAb6H4 increases plasma and decreases brain methamphetamine concentration when administered either before or 30 min after a mole equivalent dose of methamphetamine [34,35]. mAb6H4 increases methamphetamine

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serum protein binding almost 20-fold and reduces the concentration of the methamphetamine metabolite amphetamine, suggesting that methamphetamine pharmacokinetic changes are occurring because of high-affinity binding to the antibody, rather than increased catabolism [36]. Pretreatment with mAb6H4 protects rats against the locomotor and cardiovascular effects of a mole-equivalent dose of methamphetamine [37] and reduces methamphetamine self-administration [38]. Pretreatment with a similar antimethamphetamine mAb, mAb6H7, blocks the ability of trained pigeons to discriminate methamphetamine from saline [39]. The high-affinity antiPCP antibody mAB6B5 (KD = 1.3 nM) similarly increases plasma and decreases brain PCP concentrations, protects against the locomotor and toxic effects of PCP [40–42] and blocks the ability of trained pigeons to discriminate PCP from saline [39]. The protective effect may last up to 2 weeks after a single mAb injection [43] and can occur with an antibody dose as low as one-hundredth the molar equivalent of the total body PCP burden [40]. These findings suggest that mAb treatment might be effective at lower doses than the equivalent total drug dose (thus making it more affordable) and might be harder than expected to overcome by increasing drug intake to saturate drug binding sites. A highly specific, high-affinity mouse antinicotine mAb (NIC311; KD = 60 nM) has been shown to reduce nicotine distribution into rat brain shortly after intravenous nicotine administration, although it did not reduce chronic brain accumulation over 2 days of nicotine dosing [44]. Slowing entry of nicotine into the brain may reduce its rewarding subjective effects [2], thus contributing to therapeutic efficacy of the mAb. A practical issue for clinical use of antidrug mAbs is costeffective, large-scale production to good manufacturing practice standards. In some clinical settings, doses of several grams may be needed for clinical effectiveness. mAbs for preclinical research are produced by expression in mammalian cells grown in cell culture, a method more efficient at producing full-length mAbs than Fab or scFv [27]. scFv is easier to express than the multichain full-length antibody or Fab, and so may be more cost effective for large-scale production [45]. Production by expression in bacteria, yeast and plants is currently being explored. InterveXion Therapeutics is evaluating large-scale production of its anti-PCP and antimethamphetamine mAbs in alfalfa plants. An alternative approach to peripheral binding of drug molecules in the blood with free antibodies is the use of antibodycontaining particles that can reach the brain after peripheral administration. This has been accomplished by expressing the anticocaine mAB GNC92H2 on the protein coat of filamentous bacteriophage viruses [46]. When administered intranasally to rats, these viruses penetrate the brain and significantly reduce the locomotor and stereotyped behavioral responses to intraperitoneal cocaine for up to 4 days. Whether this route of administration improves efficacy over peripheral administration remains unknown.

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Enhanced drug metabolism

The goal of enhanced drug metabolism is to break down enough drug molecules quickly enough to get drug levels below the minimum effective concentration at the site of action. Current research focuses on enhanced metabolism of cocaine, which is readily hydrolyzed at the benzoyl moiety into inactive metabolites (ecgonine methyl ester and benzoic acid). Enhanced cocaine metabolism has been achieved by two approaches: drug-metabolizing enzymes and catalytic mAbs. Both approaches allow the use of recombinant genetic techniques to engineer agents with optimized catalytic properties. Monoclonal antibodies have been reported that catalyze the oxidative degradation of methamphetamine [47] and nicotine [48] in vitro in the presence of riboflavin. There is no published in vivo work with these enzymes. Drug-metabolizing enzymes

Several types of naturally occurring esterases metabolize cocaine. These include butyrylcholinesterase (BChE) (EC 3.1.1.8, previously known as pseudocholinesterase or serum cholinesterase), a cocaine esterase from the bacterium Rhodococcus strain MB1 [49] and carboxylesterase (EC 3.1.1.1) [50]. There is no published development work with the latter enzyme. Butyrylcholinesterase

Initial research efforts focused on BChE, a major cocainemetabolizing enzyme in primates that is widely distributed in the body [51]. Case reports of successful use of partially purified human BChE (derived from blood) to treat toxicity from neuromuscular blocking agents, such as succinylcholine and mivacurium (which are also hydrolyzed by BChE), suggested that administration of exogenous BChE would not raise safety issues, such as stimulation of an antienzyme immune response. Animal studies showed that BChE administration substantially increased cocaine metabolism and reduced brain cocaine concentrations, while BChE pretreatment or short-term post-treatment significantly reduced the acute behavioral, cardiovascular and toxic effects of a cocaine challenge [51,52]. However, (-)cocaine, the naturally occurring active enantiomer, is not a preferred substrate for BChE, with a catalytic efficiency (k cat/Km) of only 9 × 105 M min -1 (TABLE 3). The limitation of high dose requirements, with resulting high cost and limited availability, have stimulated efforts to genetically engineer an improved version of BChE. Site-directed mutagenesis based on molecular modeling of BChE–cocaine transition state complexes [53] has been used to create BChE variants (cocaine hydrolases) with better hydrolysis of (-)cocaine than the wild-type enzyme. One double mutant variant, Ala328Trp/Tyr332Ala, has a catalytic efficiency of 8.6 × 106 M min-1, approximately ninefold better than the wild-type enzyme (TABLE 3) [54]. Pretreatment with this enhanced enzyme substantially reduces cocaine plasma half-life as well as brain and

284

heart cocaine concentrations in rats [55]. Pretreatment with the enzyme (3 mg/kg intravenously) prevented the locomotor hyperactivity and pressor effects of a cocaine challenge [55,56]. Post-treatment with the enzyme rapidly reversed the established pressor effect of a cocaine challenge [55]. To prolong the duration of enzyme action, a research group has inserted cloned DNA coding for the enzyme into a replication-incompetent adenovirus vector [57]. Intravenous injection of the viral vector into rats resulted in enzyme activity appearing in liver and plasma after 2 days, with peak plasma activity after 5–7 days equivalent to an intravenous injection of 3 mg/kg of purified enzyme. Enzyme transduction occurred primarily in the liver, with little or none detected in the brain, heart or other organs [57]. The animals developed hepatitis, most likely due to an immune response to the enzyme. A quadruple mutant (Phe227Ala/Ser287Gly/Ala328Trp/ Tyr332Met) variant of BChE has been developed by Applied Molecular Evolution (San Diego, CA, USA; now a subsidiary of Eli Lilly) [58]. AME359 has a catalytic efficiency of 3.1 × 107 M min-1, more than 30-fold better than the wild-type enzyme (TABLE 3) [57]. Pretreatment of rats with 0.5 mg/kg intravenously completely prevented the lethal effects of a 2-mg/kg/min cocaine infusion (which killed 100% of untreated rats within 12 min). Intravenous pretreatment of rats with an adenovirus vector containing cloned DNA coding for AME359 resulted in a 95% decrease in plasma cocaine concentration 4 min after an intravenous cocaine challenge 5 days later (compared with control rats). Cocaine brain uptake was reduced by approximately half, heart uptake by almost 90% and the pressor effect of cocaine was almost completely prevented [57]. Injection of viral vector directly into the nucleus accumbens resulted in substantial esterase activity on and around basal forebrain neurons 6 days later [59]. A further improved quadruple BChE mutant (Ala199Ser/Ser287Gly/Ala328Trp/Tyr332Gly) has been developed [60]. In vitro studies confirmed that this variant had a catalytic efficiency of approximately 4.1 × 108 M min-1, approximately 450-times better than that of wild-type BChE (TABLE 3). A plasma concentration of the variant enzyme equivalent to that of the endogenous wild-type enzyme should shorten the plasma half-life of cocaine to approximately 6–12 s, a reduction likely to be clinically meaningful. No in vivo studies with this variant have been published. Bacterial esterase

Rhodococcus bacteria grow in the rhizosphere soil of Erythroxylum coca, the cocaine-producing plant, and use cocaine as a source of carbon and nitrogen [49]. The MB 1 strain produces a highly active cocaine esterase with a catalytic efficiency of around 7.3 × 108 M min-1, more than 800-fold that of the wild-type BChE enzyme (TABLE 3). In human plasma spiked with 300 µM cocaine, a 0.8-µM dose of esterase reduced the cocaine concentration to 2 µM within 1 min [61]. Treatment of mice with esterase (1 mg intravenously) either 1 min before or

Expert Rev. Clin. Pharmacol. 1(2), (2008)

Pharmacokinetic approaches to treatment of drug addiction

Review

Table 3. Kinetic characteristics of drug-metabolizing enzymes. Enzyme

Catalytic rate constant (k cat) (min-1)

Michaelis constant (K m) (µM)

Catalytic efficiency (kcat/Km)

BChE wild-type

4.1

4.5

9 x 10 5

BChE double mutant*

154

18

8.6 x 106

20

7

BChE quadruple mutant (AME 359) BChE quadruple mutant

‡

620

§

Bacterial esterase

3.1 x 10

~ 4.1 x 10 468

0.64

7.3 x 10

8

Improvement over wild-type BChE

∼ Ninefold ∼ 34-fold 8

∼ 450-fold ∼ 800-fold

*

Ala328Trp/Tyr332Ala. Phe227Ala/Ser287Gly/Ala328Trp/Tyr332Met. Ala199Ser/Ser287Gly/Ala328Trp/Tyr332Gly. BChE: Butyrylcholinesterase. ‡ §

after an intraperennial cocaine challenge almost completely prevented convulsions and death [61]. Earlier pretreatments had a declining effect, presumably because plasma esterase activity had a half-life of 13 min. Post-treatment with esterase (1 mg intravenously) almost immediately stopped cocaine-induced convulsions and completely prevented the deaths that occurred in untreated animals [62]. However, esterase was less effective after four prior exposures and these mice had high titers of antiesterase antibodies [62], suggesting that the enzyme was immunogenic. Pegylation of the esterase (i.e., attaching strands of polyethylene glycol polymer) or packaging it in red blood cells (which have a normal in vivo lifespan of around 4 months) have been proposed as methods to reduce immunogenicity and prolong half-life [63]. Catalytic antibodies

Catalytic antibodies were developed to avoid a potential limitation of conventional anticocaine antibodies, namely, possible saturation of the passive binding sites by increasing cocaine doses. They bind noncovalently to their antigen then, like an enzyme, catalyze hydrolysis of the cocaine molecule [64]. This frees the antibody to bind and hydrolyze another cocaine molecule. A variety of anticocaine catalytic antibodies have been generated [65], most with catalytic properties less favorable than those of BChE variants or the bacterial cocaine esterase. The most studied is the mouse mAb 15A10 [66]. Pretreatment of rodents with antibody (up to 300 mg/kg intravenously) dosedependently protects against the increased blood pressure, seizures and death produced by a cocaine challenge, and significantly shifts the dose–response curve for intravenous cocaine self-administration downward and to the right. The duration of the protective effect was less than 10 days. In an attempt to increase the duration of action, the antibody has been microencapsulated in poly(lactic-glycolic) acid microspheres [67]. This resulted in detectable blood antibodies in mice up to 10 days after subcutaneous injection.

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Clinical applications

Enhancing cocaine metabolism seems well suited for the treatment of acute cocaine toxicity or overdose because the therapeutic action should begin immediately after administration of the enzyme or catalytic antibody. Pretreatment studies in rodents suggest that, with sufficient catalytic efficiency, cardiovascular, neurological and behavioral effects of a high-dose cocaine challenge can be attenuated or even eliminated. Proof of concept for pretreatment efficacy in primates is provided by a study in which baboons received intravenous (+)cocaine [68], the inactive enantiomer, which is a preferred substrate for endogenous BChE. Hydrolysis was so effective that there was no detectable blood cocaine after 1 min and no detectable brain uptake of radiolabelled (+)cocaine. Post-treatment studies in animals have only evaluated intervals of up to several minutes after cocaine administration. In the clinical context, patients are not likely to present for treatment within minutes of ingesting cocaine. Most cocaine-associated deaths occur within 2 h of ingestion [69], so there may be a narrow window of opportunity for clinical application of enhanced cocaine metabolism. In addition, there is not necessarily a close correlation between cocaine concentrations and behavioral or toxic effects [70], so that the clinical benefits of rapid reductions in cocaine concentrations are uncertain. Further research is needed in primates, and eventually in humans, to address these questions. A practical issue for clinical use of metabolism-enhancing agents is cost-effective, large-scale production to good manufacturing practice standards. Animal studies suggest that some agents may require doses of several grams for clinical effectiveness. Methods have been developed for large-scale purification of BChE from human plasma [71]. The limiting factor is the amount of donated plasma available. An alternative may be expression of recombinant human BChE in plants (e.g., tomato and tobacco) or in the mammary gland of transgenic animals (e.g., goats), with secretion into the milk [72].

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Review

Gorelick

Ethical issues

Several ethical issues have been raised concerning use of an antidrug vaccine or antibody [3,73]. Patients would have detectable levels of antidrug antibody (or bacterial esterase) in their blood for prolonged periods, identifying them as being in treatment for addiction. This potential compromise of confidentiality risks serious adverse legal, vocational, economic and insurance consequences for patients. Should pharmacokinetic treatment be used for primary prevention in individuals at high risk for addiction (e.g., adolescents with occasional drug use) who may not be in a position to make a completely voluntary decision? What about enforced treatment in the criminal justice, child welfare or employment settings? These issues will have to be addressed as pharmacokinetic treatments are developed and gain widespread clinical use. Expert commentary

Pharmacokinetic approaches have a promising future in the treatment of drug addiction but must undergo substantial further development and clinical evaluation. High-affinity, drug-specific mAbs and high-efficiency drug-metabolizing enzymes (especially for cocaine) may be useful in the shortterm treatment of acute drug toxicity and overdose, similar to the role that antidigoxin antibodies play in the treatment of digitalis toxicity [74]. Further research is needed to evaluate their efficacy with clinically realistic postdrug administration intervals of up to several hours. The main developmental hurdles are producing humanized versions that do not themselves evoke an immune reaction and developing cost-effective methods for large-scale production. These agents may also be useful for the longer-term treatment of drug addiction, if versions with effective half-lives of weeks or longer can be developed. Antidrug vaccines may be useful for longer-term treatment of drug addiction (dependence), based on the promising initial Phase II clinical trials with anticocaine and antinicotine vaccines. They may be especially useful in patients for whom treatment compliance is an issue or who are at high risk of adverse events from conventional (pharmacodynamic) medication, such as pregnant women, those with severe medical or psychiatric comorbidity or those taking conventional medications with risk of medication interactions. Clinical studies to date show a wide range of individual immune responses to vaccination and a strong positive association between antibody titer and clinical efficacy. These findings illustrate the need for further research to develop more immunogenic vaccines and cost-effective methods for monitoring antibody titers, to determine optimum vaccination and booster schedules, and the use of adjuvants. Research is also needed to determine the optimum bridge treatment over the weeks to months until effective immunization has occurred.

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This is likely to be a combination of psychosocial treatment and medication, perhaps including passive immunization with antidrug mAbs. Fortunately, continued drug exposure during the vaccination period does not appear to prevent the mounting of a clinically relevant antibody response, so that complete abstinence during this period is not required. Five-year view

Pharmacokinetic treatments for drug addiction, while promising in animal studies and early Phase II clinical studies, are unlikely to enter routine clinical practice within the next 5 years. The most immediate to be adopted are likely to be antinicotine vaccines. The NicVAX (Nabi Biopharmaceuticals) and Nic-Qb (Cytos) vaccines appeared safe and effective in Phase II clinical trials and may enter Phase III trials by the end of 2008. Nic-Qb has already been licensed to a large pharmaceutical company (Novartis) for further development; Nabi is looking for such a partner for NicVAX. The NicVAX vaccine received fast-track approval from the US FDA in February, 2006, which should speed the approval process. Celtic Pharma expects to complete a Phase IIb clinical trial of its TA-NIC vaccine in 2008. The TA-CD anticocaine vaccine may enter a Phase III trial in 2008; Celtic Pharma is reportedly looking to sell the product to a large pharmaceutical company that could fund further development. Antidrug mAbs, catalytic antibodies and drug-metabolizing enzymes are all still in preclinical development. Their clinical use is years away. The anti-PCP mAb (InterveXin-PCP) developed by InterveXion may enter Phase I clinical trials during 2008; the antimethamphetamine mAb (InterveXin-METH) is at least a further year away from clinical trials. Even after regulatory approval, pharmacokinetic treatments will face significant barriers to widespread use. Most drugaddiction treatment in the US is delivered in public or publicly funded treatment programs that are chronically underfunded and often not medically staffed (except for methadone maintenance clinics). Thus, the high cost (estimated US$1000–2000 for a mAb dose) and need for medical staff to administer injections and monitor for side-effects may discourage the use of pharmacokinetic treatments. The mainstreaming of addiction treatment into primary care medicine and elimination of health insurance discrimination against coverage of addiction treatment would help resolve this issue. Individual patient objections to pharmacokinetic treatment may derive from concerns over inability to self-medicate drug craving or withdrawal, possible effects on the outcome of drug testing and potential breach of confidentiality from detection of antidrug antibodies or enzymes in the blood. One advantage for pharmacokinetic treatments may be greater acceptance by patients and treatment staff who oppose addiction treatment medication. This opposition is based largely on belief that most such medications are potentially

Expert Rev. Clin. Pharmacol. 1(2), (2008)

Pharmacokinetic approaches to treatment of drug addiction

Review

addictive because they are psychoactive. Pharmacokinetic treatments may be more readily accepted because they target the drug molecules, not the brain, and do not themselves exert any psychoactive effects.

products is available on the websites of the companies developing them, such as TA-NIC and TA-CD vaccines [104], Nic Qb vaccine [105], NicVAX vaccine [106] and anti-PCP and methamphetamine mAbs [107].

Sources of information

Financial & competing interests disclosure

Reports on pharmacokinetic treatments in peer-reviewed journals often lag a few years behind the actual work. More up-to-date information is often available at scientific meetings (e.g., College on Problems of Drug Dependence [103] and on websites that cover the pharmaceutical and biotechnology industries). Some information regarding specific

DA Gorelick is supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Pharmacokinetic approaches are in development for the treatment of acute drug toxicity/overdose and addiction: – Targeted drugs include nicotine, cocaine, phencyclidine and methamphetamine. • Antinicotine and anticocaine vaccines in Phase II clinical trials appear promising: – High antibody titers associated with decreased drug use. – Well tolerated. • Antidrug monoclonal antibodies protect against acute drug toxicity in animal studies. • Butyrylcholinesterase genetically modified with improved catalytic properties and bacterial esterase protect against acute cocaine toxicity in animal studies. • Issues that need addressing in future research include: – Achieving consistently high, effective antibody titers after vaccination. – Determining the optimum concurrent treatments to accompany vaccination. – Evaluating the efficacy of antidrug antibodies and enzymes when administered minutes to hours after drug intake. – Minimizing potential adverse immune responses to monoclonal antibodies and drug-metabolizing enzymes by creating humanized variants.

4

Orson FM, Kinsey BM, Singh RA, Wu Y, Gardner T, Kosten TR. The future of vaccines in the management of addictive disorders. Curr. Psychiatry Rep. 9, 381–387 (2007).

••

Reviews the science of antidrug vaccines.

5

Keyler DE, Roiko SA, Benlhabib E et al. Monoclonal nicotine-specific antibodies reduce nicotine distribution to brain in rats: dose– and affinity–response relationships. Drug Metab. Dispos. 33, 1056–1061 (2005).

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Aktiv-dry www.aktiv-dry.com

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College on problems of drug dependence www.cpdd.org

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Celtic pharma www.celticpharma.com

105

Cytos biotechnology www.cytos.com

106

Nabi biopharmaceuticals www.nabi.com

107

InterveXion therapeutics www.intervexion.com

Affiliation •

David A Gorelick Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA Tel.: +1 443 631 8004 Fax: +1 443 631 8037 [email protected]

Expert Rev. Clin. Pharmacol. 1(2), (2008)