Changes in prescribed drug doses after market introduction

Abstract

SUMMARYPurpose The establishment of recommended dosing regimens has always been a difficult aspect of drug development. This paper examines the extent to which postmarketing prescribing deviates from initially recommended dosing regimens. We used the World Health Organization's (WHO) periodically updated compilation of the 'Defined Daily Dose' (DDD) to reflect prevailing patterns of prescribing in national markets. The aim of this study was to evaluate DDD changes over time (1982)(1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000) and to identify possible determinants of these changes. Methods Data on DDD changes were obtained from the WHO's Oslo Collaborating Centre. We performed a case-control analysis in which we compared drugs with (cases) and without (controls) postmarketing changes in DDD on possible determinants associated with DDD change. Results We found 115 instances of a change of DDD in the period 1982-2000 (45 (39.1%) increases and 70 (60.9%) decreases). Antibiotics showed the greatest number of changes in DDD: predominantly increases in the 1980s, while the 1990s were dominated by decreases in DDD of mostly cardiovascular drugs. Conclusion Changes in DDD reflect the outcome of a melange of forces, including misconceptions of dose requirements during pre-market development of drug and postmarketing changes in pharmacotherapeutic knowledge, clinical concepts, economic forces, and, in the case of anti-infective agents, changing patterns of resistance/sensitivity of target microorganisms to the anti-infective agent(s) in question.

Changes in the defined daily dose; CYP2D6/CYP3A metabolism as an indicator for dose-setting problems

“…In this study, the decade of registration was a strong predictor for undergoing a DDD change; this was also found in our previous study [4]. The reason for this could be that, because of the extensive experience with drugs marketed before 1970, good dosing strategies had already been developed in clinical practice long before the DDD methodology was introduced in the mid-1970s.…”

“…When Cross et al studied labelling changes of New Molecular Entities in the United States approved by the Food and Drug Administration between 1980 and 1999, they found that one in five compounds underwent a dosage change after marketing [3]. Our group has previously reported on 115 changes in the defined daily dose (DDD)-a dose measure developed and maintained by the World Health Organization (WHO)-and came basically to the same conclusion [4]. DDD increases were most frequently associated with antibiotics, while cardiovascular drugs underwent more dose decreases.…”

“…We used a design comparable to that used in the previously mentioned study on DDD changes [4]. Again, we made use of a case-control design for the analysis.…”

“…Year of global introduction of a drug was ascertained, since this was a determinant in the previous study [4]. Information on whether drugs were substrates of the CYP2D6/CYP3A enzymes was retrieved from the so-called 'Flockhart' CYP drug-interaction table [11].…”

“…DDD increases were most frequently associated with antibiotics, while cardiovascular drugs underwent more dose decreases. An important finding from both studies was that newer drugs were more susceptible to postmarketing dose changes than older drugs [3,4].…”