Novel Method To Assess Antiretroviral Target Trough Concentrations UsingIn VitroSusceptibility Data

Abstract

Fully suppressive antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection requires the administration of drug combinations that target multiple sites on one or more proteins required for viral replication. Approved antiretrovirals (ARVs) include nucleoside/nucleotide and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively), protease inhibitors (PIs), entry inhibitors, and integrase strand-transfer inhibitors (INSTIs). With the exception of the NRTIs, which require intracellular phosphorylation, plasma drug concentrations are correlated with drug efficacy. At the same time, high drug concentrations are associated with excess toxicity.To durably suppress HIV replication in infected patients, ARV concentrations must reach and be maintained at levels that exceed the susceptibility of the virus to that drug. Treatment response is often hampered by the failure to achieve sufficient drug exposure (i.e., poor adherence and drug interactions), reduced drug susceptibility (i.e., viral drug resistance), or both. Drug concentrations within patients vary over time and, due to ease of sampling, are generally characterized by minimum (trough) concentrations (C trough ) immediately prior to administration of the next scheduled dose. Drug concentrations also vary considerably between individual patients as a result of differences in absorption, distribution, metabolism, and excretion. In addition, each drug characteristically binds to human plasma proteins to different extents. Furthermore, the susceptibility of HIV-1 variants, even in patients not previously exposed to drug therapy, varies over a range that is unique to each drug (23,24,46).In vivo clinical pharmacodynamic data are available for some, but not all, ARVs. Efficient collection of these data is difficult and ideally performed early in the drug development process. Alternative methods of incorporating ARV pharmacokinetics into therapeutic decision making are being explored. In vitro phenotypic drug susceptibility testing of individual patient viruses is now widely available and generates information that can be used to calculate an inhibitory quotient (IQ), defined as the ratio between the C trough and the drug concentration that inhibits in vitro replication by a defined percentage (e.g., 50% or 95% inhibitory concentration [IC 50 or IC 95 , respectively]) (27,35,43,56). Derivatives of the IQ, including the genotypic IQ (GIQ; C trough divided by the number of resistance-associated mutations for a given drug) have also been evaluated (36). Several studies have attempted to define the optimal IQ required to produce long-term viral suppression: in some cases, IQ has been retrospectively linked to clinical outcome (15,34,41,42,55), while in others, direct relationships between IQ and viral load response were not observed (5, 12).For most ARV drugs, few or no in vivo concentration-response data have been generated, or these data are inconsistent with clinical observations. Collectively, there is insufficient agr...

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

“…Although it is highly desirable to assess activity in the presence of 100% serum, the potency at 100% serum is often extrapolated from the potency determined at a lower percentage of serum, assuming a linear relationship between inhibitory potency and serum concentration. Depending on the degree of hydrophobicity, however, the correlation is often not in a linear relationship, especially for highly protein-bound compounds, such as NNRTIs (17). Therefore, the potency obtained from the extrapolation does not accurately reflect the potency in 100% serum.…”

“…For highly protein-bound inhibitors, in vitro antiviral potencies shift significantly when the assays are conducted in the presence of 50% serum compared with 10% serum (14)(15)(16)(17). Although it is highly desirable to assess activity in the presence of 100% serum, the potency at 100% serum is often extrapolated from the potency determined at a lower percentage of serum, assuming a linear relationship between inhibitory potency and serum concentration.…”

Evaluation of the Effect of Cobicistat on theIn VitroRenal Transport and Cytotoxicity Potential of Tenofovir

“…As the free fractions of both COBI and RTV in human serum reach only 2 to 5% of the total concentration (data not shown) due to extensive binding by serum proteins, including albumin and ␣-acid glycoprotein, the serum proteins will decrease the availability of both drugs for interacting with MRP4. Cell-based assays in the presence of human serum are frequently used to test the interactions of drugs with intracellular targets in a more physiological environment (20,21). To directly test the effect of protein binding, the inhibition of MRP4 by COBI and RTV was evaluated in the presence of 100% human serum.…”

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

“…If multiple drug treatment are considered, an algorithm for the combined effect is used 21. The in vitro to in vivo extrapolation of drug effect needed to account for the plasma protein binding effect on the IC 50 ( k p ), and for lymph node drug penetration ( k l ) 8, 22…”