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European Biopharmaceutical Review

The PK/PD Complex

Recent clinical presentations reveal that researchers are increasingly investigating the pharmacokinetic (PK) and pharmacodynamic (PD) properties of anti-infective drugs. The key to evaluating experimental compounds has been through PK and PD analyses of marketed medicines, which are shedding new light on their behaviour in particular patient populations and against specific pathogens. These insights are guiding clinicians to make better treatment decisions, and helping drug makers to improve already-valuable treatments.

Optimising Dosage

Clinicians around the globe know that certain types of patients face an elevated risk from infections. Of course, immune-compromised individuals are endangered by pathogens, whether bacterial or fungal. However, people with relatively common morbidities, such as renal dysfunction or obesity, may also be at particular risk from infection because their conditions complicate treatment. By acknowledging this reality, researchers are increasingly investigating whether and how they can leverage PK and PD analysis of marketed drugs to tailor anti-infective treatment protocols to improve patient outcomes.

International researchers have been reporting on the efforts to harness PK/ PD data on behalf of particular patient subtypes. For example, teams from the US and Egypt worked together to draw conclusions about how best to dose the antibiotic daptomycin in haemodialysis (HD) patients. Infections are the second-leading cause of death in chronic HD patients. Powerful anti-infective drugs, such as daptomycin, always require physicians to seek a balance between a treatment’s efficacy at killing off bacteria and its toxicity. Not surprisingly, the challenge is heightened in patients whose kidneys are poorly functioning.

Recent studies assessed the PK/PD and clinical ramifications of treating dialysis patients before, during and after HD, with various dosages of daptomycin (1-3). The researchers found that administering 6mg of the drug during or after HD, but not before it, at 48-hour intervals achieved the best cumulative and daily efficacy measurements (AUC levels) with minimal toxicity. But if patients received daptamycin and HD at 72-hour intervals, the data showed that the drug dosage had to be boosted from 6mg to 9mg, to achieve similar efficacy levels.

Researchers looking to improve outcomes in HD patients given the antibiotic vancomycin found it was possible to maintain effective blood concentrations of the drug by adjusting dosage for body weight. Another study noted that while blood levels of 10mg/L are considered beneficial for fighting infection, little data exists about how to actually achieve that level (4). The study reported data from collaborators at six institutions, who studied HD patients from 18-75 years old with Staphylococcus aureus infections. It found that dosing 10mg of drug per kg of body weight kept blood levels of vancomycin from dipping below the recommended level of 10mg/L.

Healing of Specific Tissues

Sometimes, higher doses of anti-infective drugs boost efficacy, but it does not necessarily help and could prove harmful – depending on the organism and where a compound travels in the body. Professor of Therapeutics and Infectious Diseases, William W Hope, reminded an audience that a PD target is not a physical thing, but rather a measure of exposure that splits the patient population into odds of good or bad outcome (5). Setting the target is not an exact science, he said: it is up to the clinician to decide whether a 50 per cent or a 90 per cent drop in fungal burden is important, or some other goal, such as stasis, or simply patient survival.

“The PD target is context-dependent,” Hope declared, “and it changes according to the clinical condition,” such as when a patient’s Candida infection is systemic or localised in the eye. The treatment decision hinges not only on the organism, but on the drug and what is known about it. He pointed out: “The dogma holds that echinocandins [a widely-prescribed class of antifungal drugs] do not get to the eye, so you could boost drug levels till it hurts the kidney and still not help the eye.” The patient’s overall health also influences treatment decisions, Hope said, noting for instance that, “Neutropenia [lack of white blood cells] enables fungal infection.” Because white cells are ordinarily vital to host defense, “you need a lot more drug to ensure a favourable outcome in consistently neutropenic mice”.

Growing numbers of researchers are doing PK and PD analysis of drug concentrations in various tissue types, to see whether a given compound has any chance at helping certain types of infection and if so, what dosing levels give the best odds of success. Scientists from Keio University in Japan recently reported on their study of the aminoglycoside antibiotic arbekasin sulfate, marketed in Japan since 1990 and now available as a generic (6). The drug has shown activity against methicillin-resistant Staphylococcus aureus, the researchers said.

They pointed out that PK/PD theory holds that a drug’s efficacy is determined by serum concentration levels (C-max) of a drug, but they believed local concentration in the epithelial lining fluid (ELF) would more precisely estimate efficacy in respiratory infections. So they measured both. Half an hour after infusion of arbekasin, concentration in the ELF was half that found in the serum – a sufficient amount to kill ordinary respiratory pathogens, they concluded. A “practical amount of Arbekacin (ABK) could be appropriate for the treatment of MRSA-pneumonia”, they asserted, while acknowledging that PK results would be different in people with pneumonia than in the healthy volunteers who participated in this study.

Brain Infections

Joanne Livermore of the University of Liverpool recently reported intriguing PK/PD data from a study designed to investigate why an abbreviated regimen of Amphotericin B (three daily doses) produces similar antifungal results to prolonged administration (seven daily doses) in a well-validated murine model of cryptococcal meningitis (7). This type of infection is a leading cause of mortality and morbidity in AIDS patients, in resource-poor settings. The researchers hypothesised that the effect could be due to the drug’s persistence in the brain, or perhaps to an immune response sparked by the brief treatment, but they did not know for sure and felt it necessary to understand before recommending the shorter treatment protocol be tested in humans.

To understand what Amphotericin B does in the body (of mice, at least), the researchers measured the percentage of CD3, CD4 and CD8 cells in the brain, the spleen and plasma. They also measured drug concentration levels in the brain and plasma, and used quantitative culture to estimate fungal burden in the brains. The study showed that the percentage of immune cells increased only in the brains of infected, untreated mice, while the drug was quantifiable in the brain the whole time it was being administered, and for four days afterwards.

The researchers were thus able to conclude that the antifungal activity from the shorter course of drug treatment came about because Amphotericin B persists in the brain tissue. This PK/PD analysis has immediate implication for humans suffering with potentially deadly fungal brain infections: if getting a good outcome is possible with a lower dose of this expensive drug, it may be more feasible to treat patients with it in low-resource settings.

Delivery Changes

Intravenous (IV) infusion is currently the standard way of delivering antibiotics to patients with severe bone infections or osteomyelitis. The condition is notoriously difficult to treat, in part because antibiotics are poor at penetrating bone. The clinical challenge is only getting worse as pathogens become increasingly resistant to known drugs. Scientists from the University of Nantes in France believe they have found a better way of treating bone infections: by combining antibiotics with granules of calcium-deficient apatite (CDA), a bone-like natural substance with osteoconductive properties, and slathering the mixture at the site of infection.

Efforts to treat acute osteomyelitis caused by MRSA with varying doses of daptomycin mixed with granules of CDA have been recently reported (8). The study carried out in a rabbit model compared results of this treatment to IV administration alone and untreated controls. As it turned out, the IV daptomycin on its own had no influence on infection after four days. But subjects given the drug by IV plus drugloaded granules of CDA obtained what researchers deemed ‘excellent results’, showing the method worthy of adapting for humans.

Similar to implementing a new approach to delivery, changing a drug’s formulation can also remedy PK problems known to limit efficacy, as Rafael Duarte of the Catalan Institute for Oncology in Barcelona, Spain says (9). To prove this point, he recently shared PK/PD data on a new solid, oral version of the antifungal drug posaconazole, originally formulated as a solution. Duarte’s study showed that the new tablet formulation improves the drug’s biovailability beyond the original, so that a 300mg dose of the solid oral drug put 90 per cent of patients in therapeutic range. “This should fix the acknowledged problem of the original drug,” he declared, explaining that swings and gaps in bioavailability can mean that patients receive substandard therapy, even when given sanctioned doses, because not enough of the drug is present to combat fungus.

Basing Clinical Decisions on PK/PD

Numerous studies make clear that insights into the PK profiles of drugs can help clinicians make better decisions about which drugs to prescribe, and at what doses, for particular kinds of patients. Increasingly, clinical studies of marketed drugs are yielding an understanding that may supersede the labelling information on a package insert, or even physicians’ past experience with a specific product or class of products.

A study revealed that a patient’s body weight can alter the PK and PD characteristics of drugs in unhelpful ways that clinicians need to be aware of (10). In what the researchers said is “the largest prospective case study of measured broad-spectrum beta-lactam serum levels in infected, obese, non-critically ill patients,” the study team found that subjects given standard doses of antibiotics seldom achieved serum levels of drug sufficient to provide adequate therapy against “difficult-to-treat” Gram-negative organisms.

In the Belgian study, 29 out of 38 drug levels taken from 29 patients fell below the parameter of four to eight times minimum inhibitory concentration (MIC), defined as adequate by EUCAST, the European Committee on Antimicrobial Susceptibility Testing. The worrying result reached across all four of the beta-lactam antibiotics given during the course of the study: cefapime or ceftazidime; piperacillin-tazobactam or meropenem. Study authors made no recommendations as to how to boost serum levels in obese patients, but suggested that dosing regimens be reconsidered.

PK studies can allay worries, too, which was seen in the research from Thomas Jefferson University in Philadelphia and at Merck. The collaborators showed that commonly prescribed antacid drugs, such as H2 blockers and proton-pump inhibitors, have no effect on the PK of the new solid oral formulation of posaconazole (11). Previously, drugs in these classes were observed to alter the bioavailability of the original antifungal compound, potentially dropping serum levels and thereby limiting efficacy. This fresh data suggests that, going forward, clinicians can feel confident prescribing the new formulation for patients who take these common medications.

Conclusion

PK and PD analysis of marketed drugs is revealing clinically relevant distinctions in the way products interact with particular pathogens, tissue types and patient cohorts. Clinicians can leverage insights into the PK/PD properties of drugs to choose medicines most likely to be effective for particular sorts of infections and patients. By paying attention to PK/PD data, drug makers can develop improved products that are needed now more than ever, given the increasing rates of drug resistance worldwide.

References

1. Salama NN et al, Single-dose daptomycin pharmacokinetics in chronic haemodialysis patients, Nephrol Dial Transplant, 2010

2. Benziger DP et al, Pharmacokinetics and safety of multiple doses of daptomycin 6 mg/ kg in noninfected adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis, Clin Nephrol, 2011

3. Patel N et al, Use of pharmacokinetic and pharmacodynamic principles to determine optimal administration of daptomycin in patients receiving standardized thrice-weekly hemodialysis, Antimicrob Agents Chemother, 2011

4. Ezdon D et al, Hahnemann Hospital, Philadelphia, ICAAC 2012

5. Hope WW, ICAAC, Pharmacodynamics of Antifungal Agents, University of Liverpool, 2012

6. Funatsu Y et al, ICAAC, Penetration of Arbekacin Sulfate to the lung tissue, 2012. Visit: http://icaac.posterview.com/ pdfs/A-038.pdf

7. Livermore J et al, The antifungal activity of an abbreviated regimen of amphoterian B Deoxycholate for cryptococcal meningitis is due to persistence of drug in the brain rather than T-cell recruitment, ICAAC, 2012. Visit: http://icaac.posterview.com/ pdfs/M-977.pdf

8. Amador G et al, A new experimental model of acute osteomyelitis due to methicillin-resistant Staphylococcus aureus in rabbit, University of Nantes, UFR Medecine, France, 2010

9. Duarte R, Report from the 4th Trends in Medical Mycology Meeting (TIMM- 4), Catalan Institute for Oncology in Barcelona, Spain

10. Hites et al, Standard dosage regimens of broad spectrum beta-lactams are inadequate to treat, difficult-to treat, pathogens in obese, non-critically ill patient, The Free University of Brussels, ICAAC. Visit: http://icaac.posterview.com/ pdfs/A-637.pdf

11. Kraft WK et al, ICAAC, Effect of concomitant medications affecting gastric pH and motility on Posaconazole tablet Pharmacokinetics, 2012


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Deborah Erickson has been writing about science, medicine and business for over two decades. Her work regularly appears in international publications geared to biopharmaceutical experts, such as Elsevier’s Start-Up magazine, IN VIVO and The Pink Sheet, as well as Fierce outlets and specialised medical journals. As a Deputy Director of the Institute for the Future, she analysed the roles of key participants in the US healthcare system. Deborah began reporting on biotechnology from a business perspective when this field of science was just beginning to be commercialised, and she continues to enjoy monitoring the industry’s evolution in ways helpful to others.

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